Case#: Xin_Patient_4, sex not mentioned, age 12 at time of study, U.S. nationality, ethnicity listed as Hispanic

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient is believed to be homozygous for the NM_006493.4(CLN5):c.936del (p.Phe312LeufsTer4) variant as well as the NM_006493.4(CLN5):c.956A>G (p.Lys319Arg) variant (considered likely benign). The proband is also apparently homozygous for two non-coding variants (an intron 1 variant referred to as "Int1, c.320+8C>T" and a 3'UTR variant referred to as "3'UTR c.1224+33A>G").

ClinVar: 56528 and 128778 (in cis, homozygous)

gnomAD: Maximum allele frequency for the NM_006493.4(CLN5):c.936del (p.Phe312LeufsTer4) variant is 0.0001159 (Latino / Admixed American population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77574958-AT-A Maximum allele frequency for NM_006493.4(CLN5):c.956A>G (p.Lys319Arg) is 0.4186 (in the African / African-American population, 2136 homozygotes). https://gnomad.broadinstitute.org/variant/13-77574983-A-G

VariantEvidence: NM_006493.4(CLN5):c.936del (p.Phe312LeufsTer4) is a frameshift variant predicted to disrupt ~13% of the protein product. The C-terminal region disrupted has been shown to be glycosylated and is important for proper localization of the protein (PMID:19309691).

CaseAddInfo: Parents are not available for genotyping, so homozygosity of variants is assumed. This conclusion was supported by failure to detect a deletion.

CasePMIDs: N/A

Case#: Xin_Patient_8, sex not mentioned, age 5.5 at onset, U.S. nationality, Indian ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000512 (Abnormal electroretinogram), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset)

CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 5.5). Cognitive regression (age 6), and visual findings (abnormal ERG) had later onset.

CaseNotHPOs: HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)

CaseNotHPOFreeText: The electron microscopy findings referred to above (from conjunctiva biopsy) were normal.

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient is believed to be homozygous for the NM_006493.4(CLN5):c.428A>G p.Asn143Ser variant.

ClinVar: 56539 (homozygous)

gnomAD: The NM_006493.4(CLN5):c.428A>G p.Asn143Ser variant is absent from gnomAD.

VariantEvidence: NM_006493.4(CLN5):c.428A>G p.Asn143Ser is a missense variant at a highly conserved residue, and is speculated by the authors to function as an exonic splicing enhancer. SpliceAI finds some evidence of a possible donor loss (change score of 0.02) or acceptor gain (change score of 0.09).

CaseAddInfo: Parents have not been subjected to genotyping, so homozygosity of variants is assumed. This conclusion was supported by failure to detect a deletion. Family history of non-consanguinity or consanguinity was not mentioned, but both parents share the same local area of origin within India.

CasePMIDs: N/A

Case#: Xin_Patient_10, sex not mentioned, age 5 at onset, U.S. nationality, Pakistani ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 5). Cognitive regression and Seizures had onset at age 5, while Visual loss had onset at age 24.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient is believed to be homozygous for the NM_006493.4(CLN5):c.379dup p.Thr127AsnfsTer11 variant.

CAID: CA611398060 (homozygous)

gnomAD: The maximum allele frequency for the NM_006493.4(CLN5):c.379dup p.Thr127AsnfsTer11 variant is 0.00003266 (jn the South Asian population, with no homozygotes).

VariantEvidence: NM_006493.4(CLN5):c.379dup p.Thr127AsnfsTer11 is a frameshift variant that disrupts ~65% of the protein product and is likely to trigger nonsense mediated decay.

CaseAddInfo: Parents have not been subjected to genotyping, so homozygosity of variants is assumed. This conclusion was supported by failure to detect a deletion, and by family history of consanguinity.

CasePMIDs: N/A

Case#: Xin_Patient_1, sex not mentioned, age 5 at onset, U.S. nationality, ethnic admixture of French / Canadian / Irish / U.K. / Dutch

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset)

CaseHPOFreeText: Motor difficulty and visual loss were the phenotypes at presentation (age 5). Seizure and cognitive regression had onset at age 7.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient harbors the NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) and NM_006493.4(CLN5):c.956_959del (p.Lys319fs) variants.

ClinVar: 56544 and 56529

gnomAD: Maximum allele frequency for NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) is 0.00003517 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77570221-G-A Maximum allele frequency for NM_006493.4(CLN5):c.956_959del (p.Lys319fs) is 0.0001148 (in the African / African-American population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77574979-CACAA-C

VariantEvidence: NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) is a nonsense variant that results in truncation of approximately 51% of the protein product. The NM_006493.4(CLN5):c.956_959del (p.Lys319fs) variant triggers a frameshift that affects the final 40 amino acids (approximately 11%) of the protein product. While both variants occur in the final exon (exon 4) and neither is predicted to trigger NMD, the C-terminal region disrupted in both cases has been shown to be glycosylated and is important for proper localization of the protein (PMID:19309691).

CaseAddInfo: Parents do not appear to have been genotyped, so it is not clear whether the two variants are confirmed to be in trans.

CasePMIDs: N/A

Case#: Xin_Patient_9, sex not mentioned, age 6 at onset, U.S. nationality, Egyptian ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset), HP:0003736 (Autophagic vacuoles)

CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 6). Cognitive regression, Seizures, and Visual loss had onset at age 7. EM finding of vacuoles was made specifically in muscle.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient is believed to be homozygous for the NM_006493.4(CLN5):c.772del p.Arg258GlufsTer29 variant.

ClinVar: 56546 (homozygous)

gnomAD: The NM_006493.4(CLN5):c.772del p.Arg258GlufsTer29 variant is absent from gnomAD.

VariantEvidence: NM_006493.4(CLN5):c.772del p.Arg258GlufsTer29 is a frameshift variant that disrupts ~28% of the protein product.

CaseAddInfo: Parents have not been subjected to genotyping, so homozygosity of variants is assumed. This conclusion was supported by failure to detect a deletion, and by family history of consanguinity.

CasePMIDs: N/A

Case#: Xin_Patient_2, sex not mentioned, age 5-6 at onset, U.S. nationality, admixed European non-Finnish ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Seizure was the phenotype at presentation (age 5). Motor difficulty, visual loss, and cognitive regression had onset at age 6.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient harbors the NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) and NM_006493.4(CLN5):c.760_947del (p.Thr254CysfsTer10) variants.

ClinVar: 56544

CAID: CA2017997733

gnomAD: Maximum allele frequency for NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) is 0.00003517 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77570221-G-A The NM_006493.4(CLN5):c.760_947del (p.Thr254CysfsTer10) variant is not found in gnomAD.

VariantEvidence: NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) is a nonsense variant that results in truncation of approximately 51% of the protein product. The NM_006493.4(CLN5):c.760_947del (p.Thr254CysfsTer10) variant triggers a frameshift that affects the final 106 amino acids (approximately 29%) of the protein product. While neither variant is predicted to trigger NMD, the C-terminal region disrupted in both cases has been shown to be glycosylated and is important for proper localization of the protein (PMID:19309691).

CaseAddInfo: Parents do not appear to have been genotyped, so it is not clear whether the two variants are confirmed to be in trans.

CasePMIDs: N/A

Case#: Xin_Patient_7, sex not mentioned, age 4 at onset, U.S. nationality, Chinese ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset)

CaseHPOFreeText: Visual loss was the phenotype at presentation (age 4). Motor difficulty (age 5), Cognitive regression (age 5), and Seizure (age 6) had later onset.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient harbors the NM_006493.4(CLN5):c.473G>C (p.Trp158Ser) and NM_006493.4(CLN5):c.924_925del (p.Leu309AlafsTer4) variants.

ClinVar: 56542, 56526

gnomAD: Both the NM_006493.4(CLN5):c.473G>C (p.Trp158Ser) and NM_006493.4(CLN5):c.924_925del (p.Leu309AlafsTer4) variants are absent from gnomAD.

VariantEvidence: NM_006493.4(CLN5):c.924_925del (p.Leu309AlafsTer4) is a frameshift variant that disrupts approximately 14% of the protein product. The NM_006493.4(CLN5):c.473G>C (p.Trp158Ser) missense variant affects a conserved residue but does not have other evidence of gene impact.

CaseAddInfo: Parents do not appear to have been genotyped, so it is not clear whether the two variants are confirmed to be in trans.

CasePMIDs: N/A

GroupName: Xin_2010_Group_1

GroupPresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration)

GroupNotHPOs: N/A

NumberMales: Not mentioned

NumberFemales: Not mentioned

CountryOrigin: United States (9 patients) or Sweden (1 patient)

Ethnicity: The 10 patients had various ethnicities; Admixture of French Canadian / Irish / U.K. / Dutch, Admixture of European non-Finnish (3 individuals), Hispanic, Chinese, Indian, Egyptian, Pakistani, Swedish

Race: Not mentioned

AgeRange: Between 4 and 17 years of age at onset

TotalNumber: 10

FamilyInfo: 0

NoFamily: 10

VariantCount: 10

NonVariant: 0

OtherVariant: 0

GroupPreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

GroupMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

GroupMethod2: as mentioned

GroupGenotypingMethod: 47 original patients with an NCL phenotype but no variant in one of the 5 tested loci were subjected to CLN5 genotyping. PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. 10 patients were identified as harboring CLN5 variants. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

GroupAddInfo: N/A

Case#: Xin_Patient_5, sex not mentioned, age 17 at onset, U.S. nationality, admixed European non-Finnish ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0003581 (Adult onset), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 17). Visual loss (age 18), Cognitive regression (age 25), and seizure (age 18) subsequently developed. Granular type inclusions were observed in blood by electron microscopy. Fingerprint inclusions were observed in the brain.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing.

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient harbors the NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) variant as well as a chromosomal deletion that includes exon 4.

ClinVar: 2570 (in trans with exon 4 deletion with undefined boundaries)

gnomAD: Maximum allele frequency for NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) is 0.00002784 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77575001-A-G

VariantEvidence: The variant encodes a missense substitution that adds a cysteine to the CLN5 protein and may disrupt its structure. In a previous publication from an overlapping group of authors, mass spectrometry confirmed absence of CLN5 protein expression in samples from an individual harboring this variant, but in not control samples (PMID:19383612).

CaseAddInfo: Although parents do not appear to have been genotyped, the missense variant (in exon 4) can be inferred to be in trans with the exon 4 deletion.

CasePMIDs: N/A

Case#: Xin_Patient_3, sex not mentioned, age 17 at onset, U.S. nationality, admixed European non-Finnish ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0003581 (Adult onset), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003226 (Rectilinear intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Cognitive regression was the phenotype at presentation (age 17). Visual loss (age 20), motor difficulty (age 23), and seizure (age 23) subsequently developed. Granular type inclusions were observed by electron microscopy. Fingerprint inclusions were observed in the skin, rectilinear inclusions were observed in the muscle, and curvilinear inclusions were observed in neurons, glial cells, muscle, and spleen.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient harbors the NM_006493.4(CLN5):c.230G>A (p.Cys77Tyr) and NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) variants.

ClinVar: 2569, 2570

gnomAD: The NM_006493.4(CLN5):c.230G>A (p.Cys77Tyr) variant is not found in gnomAD. Maximum allele frequency for NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) is 0.00002784 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77575001-A-G

VariantEvidence: Both variants encode missense substitutions in the protein product. Because both change the total number of cysteines in the CLN5 protein, they may disrupt its structure. In a previous publication from an overlapping group of authors, mass spectrometry confirmed absence of CLN5 protein expression in samples from this individual, but in not control samples (PMID:19383612).

CaseAddInfo: Parents do not appear to have been genotyped, so it is not clear whether the two variants are confirmed to be in trans.

CasePMIDs: 19383612

PMID: 20157158

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

Case#: Xin_Patient_6, sex not mentioned, age 8 at onset, Swedish nationality

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0003621 (Juvenile onset), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 8). Seizures (age 8), Visual loss (age 12), and Cognitive regression (age 11) subsequently developed. Curvilinear inclusions were observed in the skin specifically.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing.

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient harbors the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) and NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variants, as well as the likely benign NM_006493.4(CLN5):c.381T>G (p.Thr127=) variant.

ClinVar: 2565, 56543, 128783

gnomAD: Maximum allele frequency for NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) is 0.00005132 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77566311-G-A Maximum allele frequency for NM_006493.4(CLN5):c.522dup (p.Trp175fs) is 0.00007033 (in the European non-Finnish population, no homozygotes). Maximum allele frequency for the NM_006493.4(CLN5):c.381T>G (p.Thr127=) variant is 0.06570 (in the East Asian population, 48 homozygotes) https://gnomad.broadinstitute.org/variant/13-77570078-T-G

VariantEvidence: The NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) nonsense variant is likely to be subject to nonsense mediated decay. The NM_006493.4(CLN5):c.522dup (p.Trp175fs) frameshift variant is predicted to truncate ~51% of the protein. On the other hand, the synonymous NM_006493.4(CLN5):c.381T>G (p.Thr127=) variant appears unlikely to have a gene impact.

CaseAddInfo: Parents do not appear to have been genotyped, so it is unclear whether the two variants with predicted gene impact have been shown or simply assumed to be in trans. The same is true for the benign, synonymous variant.

CasePMIDs: N/A

PMID: 11971870

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

ExperimentName: Intracellular localization of exogenously expressed wild-type and variant CLN5

NonPatientCell: BKH-21 cells (fibroblast-derived cell line, EFO:0002009)

GeneFunction: Localization to lysosome (GO:0005764)

GeneAlteration: The variant was introduced into the construct encoding CLN5 using site-directed mutagenesis.

FunctionalEvidence: Localization studies were performed in BHK-21 cells transiently transfected with wild-type or variant CLN5. The wild-type co-localized with lysosome and late endosome markers, while the variant co-localized with a Golgi marker (Fig. 3D–F) and showed some ER staining and vesicular-like staining. The stability of the variant following cyclohexamide treatment was also shorter than the wild-type. (Fig. 4G-4H).

FAVariants: The variant used was NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) (ClinVar:2564).

Case#: Holmberg_Patient_1, male, age 3 at onset and age 15 at time of study, Finnish origin

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0000550 (Undetectable electroretinogram), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus), HP:0001312 (Giant somatosensory evoked potentials)

CaseHPOFreeText: Age of onset was 3, while mental decline was present at age 3 and both visual deterioration and abolished ERG at age 6. The patient had progressive cerebral atrophy starting between the ages of 6 and 7. Ataxia and seizures were found at age 8. Loss of independent walking occurred at age 9. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter. Giant flash visual evoked potentials were found at age 10.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant.

ClinVar: 2564 (homozygous)

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant is 0.0008137 (within the European Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77575052-CAT-C

VariantEvidence: NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) is a recurring frameshift variant that is predicted to disrupt approximately 5% of CLN5 at the C-terminus and has been shown to disturb its localization to the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Holmberg_Patient_2, male, age 3 at onset and age 12 at time of study, Finnish origin

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0000550 (Undetectable electroretinogram), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus), HP:0001312 (Giant somatosensory evoked potentials)

CaseHPOFreeText: Age of onset was 3, while mental decline was present at age 3 and both visual deterioration and giant flash visual evoked potentials at age 6. Abolished ERG was found at age 7, and ataxia at age 8. Seizures and Loss of independent walking occurred at age 9. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant.

ClinVar: 2564 (homozygous)

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant is 0.0008137 (within the European Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77575052-CAT-C

VariantEvidence: NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) is a recurring frameshift variant that is predicted to disrupt approximately 5% of CLN5 at the C-terminus and has been shown to disturb its localization to the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Holmberg_Patient_5, female, age 4 at onset and age 7 at time of study, Finnish origin

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus)

CaseHPOFreeText: Age of onset was 4, while visual deterioration was found at age 6. Mental decline was found at age 7. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant.

ClinVar: 2565 (homozygous)

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant is 0.00005132 (within the European non-Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77566311-G-A

VariantEvidence: NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) is a recurring nonsense variant that is predicted to trigger nonsense-mediated decay of CLN5.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Holmberg_Patient_7, female, age 4 at onset and age 9 at time of study, Finnish origin with some ancestors traced to Sweden

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0000550 (Undetectable electroretinogram), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus), HP:0001312 (Giant somatosensory evoked potentials)

CaseHPOFreeText: Age of onset was 4, while mental decline, visual deterioration and abolished ERG were found at age 7. Ataxia and Seizures developed at age 8, while Loss of independent walking and Giant flash visual evoked potentials occurred at age 9. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.

CaseNotHPOs: HP:0007082 (Dilated third ventricle)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.

Variant: The patient is a compound heterozygote harboring the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) and NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variants.

ClinVar: 2564, 56543

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant is 0.0008137 (within the European Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77575052-CAT-C The maximum allele frequency of the NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variant is 0.00007033 (within the European non-Finnish population, with no homozygotes) https://gnomad.broadinstitute.org/variant/13-77570218-A-AC

VariantEvidence: NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) is a recurring frameshift variant that is predicted to disrupt approximately 5% of CLN5 at the C-terminus and has been shown to disturb its localization to the lysosome (PMID:20052765). NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) is also a frameshift variant, is predicted to disrupt ~51% of the protein product, and exhibits defective localization to the ER rather than the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Holmberg_Patient_3, male, age 3 at onset and age 19 at time of death, Finnish origin

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0000550 (Undetectable electroretinogram), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus), HP:0001312 (Giant somatosensory evoked potentials)

CaseHPOFreeText: Age of onset was 4, while mental decline, visual deterioration and abolished ERG were found at age 6. Giant flash visual evoked potentials were present at age 8, and ataxia at age 9. Seizures and Loss of independent walking occurred at age 10. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant.

ClinVar: 2564 (homozygous)

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant is 0.0008137 (within the European Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77575052-CAT-C

VariantEvidence: NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) is a recurring frameshift variant that is predicted to disrupt approximately 5% of CLN5 at the C-terminus and has been shown to disturb its localization to the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

PMID: 10953198

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

Case#: Holmberg_Patient_6, male, age 2 at onset and age 13 at death, Dutch origin

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0011421 (Death in adolescence), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0000550 (Undetectable electroretinogram), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus)

CaseHPOFreeText: This patient exhibited the most rapid clinical course from the group of 8 patients. Age of onset was 2, while mental decline was present at age 3 and visual deterioration at age 5. Ataxia, seizures, and abolished electroretinogram were found at age 7. Loss of independent walking occurred at age 8. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.

CaseNotHPOs: HP:0001312 (Giant somatosensory evoked potentials)

CaseNotHPOFreeText: Flash visual evoked potential (fVEP) was found to be normal at age 7.

CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.688G>A (p.Asp230Asn) variant.

ClinVar: 2566 (homozygous)

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.688G>A (p.Asp230Asn) variant is 0.00005437 (within the East Asian population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77574715-G-A

VariantEvidence: NM_006493.4(CLN5):c.688G>A (p.Asp230Asn) is a recurring missense variant that has been previously shown to introduce an additional N-glycosylation site within the C-terminal region of CLN5 (PMID:20052765) and to disturb its localization to the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Holmberg_Patient_8, female, age 3 at onset and age 19 at time of study, Swedish origin

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus), HP:0001312 (Giant somatosensory evoked potentials), HP:0002059 (Cerebral atrophy), HP:0001272 (Cerebellar atrophy)

CaseHPOFreeText: Age of onset was 3, while mental decline was found at age 7. Visual deterioration and Seizures developed at age 8. Ataxia and Giant flash visual evoked potentials had onset at age 9. Loss of independent walking occurred at age 10. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter. Cerebral atrophy was slight at age 8.9 years, but had progressed to severe cerebral and cerebellar atrophy by age 17.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.

Variant: The patient is a compound heterozygote harboring the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) and NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variants.

ClinVar: 2565, 56543

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant is 0.00005132 (within the European non-Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77566311-G-A The maximum allele frequency of the NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variant is 0.00007033 (within the European non-Finnish population, with no homozygotes) https://gnomad.broadinstitute.org/variant/13-77570218-A-AC

VariantEvidence: NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) is a recurring nonsense variant that is predicted to trigger nonsense-mediated decay of CLN5. NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) is a frameshift variant, is predicted to disrupt ~51% of the protein product, and exhibits defective localization to the ER rather than the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

GroupName: Holmberg_Group_1

GroupPresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus)

GroupHPOFreeText: Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

NumberMales: 4

NumberFemales: 4

CountryOrigin: Finland / Sweden / Netherlands

Ethnicity: Finnish / Swedish / Dutch

Race: Not mentioned

AgeRange: 2-4 years old at onset, 7-19 years old at time of study

TotalNumber: 8

FamilyInfo: 0

NoFamily: 8

VariantCount: 8

NonVariant: 0

OtherVariant: 0

GroupPreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.

GroupMethod1: N/A

GroupMethod2: N/A

GroupGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.

GroupAddInfo: N/A

Case#: Holmberg_Patient_4, female, age 3 at onset and age 13 at time of study, Finnish origin

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0000550 (Undetectable electroretinogram), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus), HP:0001312 (Giant somatosensory evoked potentials)

CaseHPOFreeText: Age of onset was 3, while visual deterioration was found at age 6. Mental decline was found at age 7, while abolished ERG and Giant flash visual evoked potentials were present at age 8. Ataxia, Seizures, and Loss of independent walking occurred at age 11. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant.

ClinVar: 2565 (homozygous)

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant is 0.00005132 (within the European non-Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77566311-G-A

VariantEvidence: NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) is a recurring nonsense variant that is predicted to trigger nonsense-mediated decay of CLN5.

CaseAddInfo: N/A

CasePMIDs: N/A

PMID: 16814585

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

Selection B- Expression altered in patients:

ExperimentName: Detection of CLN5 mRNA and CLN5 protein in cultured skin fibroblasts from the patient and controls

TissueExpression: Cultured skin fibroblasts (CL:0002620) or "zone of skin" (UBERON:0000014)

ExpressionEvidence: Reduced CLN5 expression by 45% at the mRNA level (Figure 6) and by 50% at the protein level (Figure 7) indicates that one of the two alleles may be subject to nonsense mediated decay and likely absence of the corresponding protein product. This may confirm the prediction that the nonsense variant NM_006493.4(CLN5):c.418C>T (p.Gln140Ter) is likely subject to nonsense mediated decay.

Case#: Bessa_Patient_1, female, age 3 at onset, Portuguese nationality

CasePresentingHPOs: HP:0000736 (Short attention span), HP:0002463 (Language impairment), HP:0002312 (Clumsiness), HP:0033044 (Motor regression), HP:0002376 (Developmental regression), HP:0000572 (Visual loss), HP:0002066 (Gait ataxia), HP:0001336 (Myoclonus), HP:0010819 (Atonic seizure), HP:0032794 (Myoclonic HP:0000648 (Optic atrophy), HP:0000546 (Retinal degeneration), HP:0012011 (EEG with occipital focal spike waves), HP:0002059 (Cerebral atrophy), HP:0001272 (Cerebellar atrophy), HP:0030891 (Periventricular white matter hyperdensities), HP:0001268 (Mental deterioration), HP:0031058 (Impairment of activities of daily living), HP:0011463 (Childhood onset), HP:0000712 (Emotional lability), HP:0002015 (Dysphagia), HP:0010864 (Intellectual disability, severe), HP:0001332 (Dystonia), HP:0007256 HP:0025357 (Erratic myoclonus), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Progressive attention deficits and regression of language ability were the phenotypes at presentation (age 3). Motor clumsiness presented at age 4, initiating a larger pattern of developmental regression. Phenotypes with onset at age 7 included visual deterioration, gait ataxia, distal and axial myoclonus, atonic and myoclonic generalized epileptic seizures, bilateral optic atrophy, retinal degeneration, abnormal EEG showing diffuse slowing of background rhythm and occipital spike-wave activity, and abnormal brain MRI with cerebral and cerebellar atrophy as well as increased signal intensity of both the posterior limb of the capsula interna and the periventricular white matter. At age 8, any independence in daily activities was lost, as well as any language abilities. Ataxic gait was marked, and EEG activity showed slowing and disorganization, frequent multifocal high-voltage polyspike-slow wave complexes, and epileptic activity corresponding to myoclonus. At 15 years (time of study), the patient was bedridden and showed amaurotic behavior, emotional lability, marked dysphagia, severe mental retardation, dystonic postures of the limbs and trunk, pyramidal signs in the limbs, bilateral optic atrophy, and frequent myoclonus (both erratic and stimulus-induced). Intracellular accumulation of autofluorescent lipopigment storage material was also detected at age 15.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotype testing was not performed. While the PPT1 and TPP1 loci were not sequenced, their enzymatic activity in extracts from leucocyte and fibroblast cells was confirmed to be within the normal range.

CaseGenotypingMethod: Based on detailed clinical phenotypes consistent with variant NCL with late-infantile onset, coding regions and intron boundaries of the CLN3, CLN5, and CLN6 loci were PCR-amplified and subjected to Sanger sequencing. Genome-wide analysis methods were not used. Parents (and patient) were subsequently genotyped using single strand conformational polymorphisms and restriction digest of PCR products, to identify variants in cis and in trans with one another.

Variant: The patient is a compound heterozygote with a paternally inherited NM_006493.4(CLN5):c.418C>T (p.Gln140Ter) variant and maternally inherited NM_006493.4(CLN5):c.688G>A (p.Asp230Asn) and NM_006493.4(CLN5):c.188G>C (p.Arg63Pro) variants.

ClinVar: 56538, 2566, 56533

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.688G>A (p.Asp230Asn) variant is 0.00005437 (within the East Asian population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77574715-G-A The NM_006493.4(CLN5):c.418C>T (p.Gln140Ter) and NM_006493.4(CLN5):c.188G>C (p.Arg63Pro) variants are absent from gnomAD.

VariantEvidence: Reduced CLN5 expression by 45% at the mRNA level indicates that one of the two alleles may be subject to nonsense mediated decay and likely absence of the corresponding protein product. This may confirm the prediction that the nonsense variant NM_006493.4(CLN5):c.418C>T (p.Gln140Ter) is likely subject to nonsense mediated decay. One of the two maternally inherited variants, NM_006493.4(CLN5):c.688G>A (p.Asp230Asn), has been previously shown to introduce an additional N-glycosylation site within the C-terminal region of CLN5 (PMID:20052765) and to disturb its localization to the lysosome (PMID:20052765).

CaseAddInfo: Parents are healthy and non-consanguineous.

CasePMIDs: N/A

PMID: 12134079

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

ExperimentName: Interaction with TPP1 and CLN3

InteractingGene: TPP1 (formerly known as CLN2) and CLN3

InteractionType: Physical (protein-protein) interaction

InteractionMethod: Co-immunoprecipitation

InteractionEvidence: PPT1 (aka CLN1), CLN3, and CLN5 were exogenously expressed in COS-1 cells. Immunoprecipitation of endogenous TPP1 (Fig. 5A) or exogenously expressed CLN3 (Fig. 5B) successfully co-immunoprecipitated CLN5 (demonstrated by western blotting). Immunoprecipitation of GST-CLN5 successfully co-immunoprecipitated TPP1 and CLN3 (Fig. 5C). This evidence helps validate the link between CLN5 variants and neuronal ceroid lipofuscinosis, as both TPP1 and CLN3 have also been linked with this disease state.

FamilyLabel: Mancini_2015_Family_ATA-7-TO

FamilyPresentingHPOs: HP:0003596 (Middle age onset), HP:0002355 (Difficulty walking), HP:0001260 (Dysarthria), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001272 (Cerebellar atrophy), HP:0006855 (Cerebellar vermis atrophy), HP:0008278 (Cerebellar cortical atrophy), HP:0001251 (Ataxia), HP:0002317 (Unsteady gait), HP:0000639 (Nystagmus), HP:0001310 (Dysmetria), HP:0007350 (Hyperreflexia in upper limbs), HP:0002395 (Lower limb hyperreflexia)

FamilyPresentingHPOFreeText: Presentation was in the middle of the 6th decade of life.

FamilyNotHPOs: HP:0410280 (Pediatric onset), HP:0003474 (Somatic sensory dysfunction)

FamilyNotHPOFreeText: N/A

CountryOrigin: Italy (North-West)

Ethnicity: Italian

Race: Not mentioned

Family#PreviousTesting: Previous testing was limited to molecular tests ruling out Friedreich Ataxia and Spinocerebellar Ataxia types 1 and 2.

Family#Method1: N/A

Family#Method2: N/A

Family#GenotypingMethod: Whole exome sequencing of the proband and the affected sibling. Homozygosity was assumed due to the consanguinity of the family, contributing to the decision to focus on the variant in CLN5. This variant was confirmed by Sanger sequencing of PCR products from exon 4 of the CLN5 gene in both affected family members and an additional unaffected sibling. Parents were not subjected to genotyping.

Affected: 2

Unaffected: 1

Segregations: 1 segregation was reported, with none inconsistent (see pedigree in Figure 1A). The patient's family is consanguineous, with the parents being first cousins.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Mancini_2015_Patient_III-5

Variant: The proband is homozygous for the NM_006493.4(CLN5):c.788G>A (p.Ser263Asn) variant.

ClinVar: 183049 (homozygous)

gnomAD: The maximum allele frequency for the NM_006493.4(CLN5):c.788G>A (p.Ser263Asn) variant is 0.000008805 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/13-77574815-G-A

FamilyAddInfo: N/A

FamilyPMIDs: N/A

Case#: Mancini_2015_Patient_III-6, female, age 52 at onset of visual symptoms, North-West Italian origin

CasePresentingHPOs: HP:0003596 (Middle age onset), HP:0002355 (Difficulty walking), HP:0001260 (Dysarthria), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001272 (Cerebellar atrophy), HP:0006855 (Cerebellar vermis atrophy), HP:0008278 (Cerebellar cortical atrophy), HP:0001251 (Ataxia), HP:0002317 (Unsteady gait), HP:0000639 (Nystagmus), HP:0001310 (Dysmetria), HP:0007350 (Hyperreflexia in upper limbs), HP:0002395 (Lower limb hyperreflexia), HP:0000736 (Short attention span), HP:0002075 (Dysdiadochokinesis), HP:0001123 (Visual field defect), HP:0030528 (Paracentral scotoma), HP:0000543 (Optic disc pallor), HP:0002346 (Head tremor)

CaseHPOFreeText: Presentation was at age 52, with visual loss (attributed to glaucoma) as the first phenotype manifested. Pale and excavated optic disc (bilateral) was consistent with severe glaucoma or previous lesion of optic nerve. Neurological symptoms were recognized at age 55 (gait instability, dysarthria, and mild cognitive deficit). Onset of slight attention deficit, nystagmus with vertical component, dysarthric slurred speech, mild head tremor, truncal ataxia, mild dysmetria and dysdiadochokinesia, ataxic gait / posture, brisk deep reflexes in all four limbs, marked cerebellar atrophy (particularly in the vermis), severe bilateral cortical atrophy (especially parietal and temporal), limited visual field (bilateral, with paracentral scotoma in the left eye only), and pale and excavated optic discs (bilateral) were found at age 58. Dysarthria worsened at age 61, when patient also exhibited an inability to walk unassisted, severe intentional tremor in the limbs, and severe cognitive impairment.

CaseNotHPOs: HP:0410280 (Pediatric onset), HP:0003474 (Somatic sensory dysfunction), HP:0002353 (EEG abnormality), HP:0040129 (Abnormal nerve conduction velocity),

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing was limited to molecular tests ruling out Friedreich Ataxia and Spinocerebellar Ataxia types 1 and 2.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Whole exome sequencing of the proband and the affected sibling. Homozygosity was assumed due to the consanguinity of the family, contributing to the decision to focus on the variant in CLN5. This variant was confirmed by Sanger sequencing of PCR products from exon 4 of the CLN5 gene in both affected family members and an additional unaffected sibling. Parents were not subjected to genotyping.

Variant: The proband is homozygous for the NM_006493.4(CLN5):c.788G>A (p.Ser263Asn) variant.

ClinVar: 183049 (homozygous)

gnomAD: The maximum allele frequency for the NM_006493.4(CLN5):c.788G>A (p.Ser263Asn) variant is 0.000008805 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/13-77574815-G-A

VariantEvidence: The variant encodes a missense substitution that results in aberrant retention in the ER compartment rather than proper localization to lysosomal vesicles (Figs. 1E-1J).

CaseAddInfo: Family is consanguineous (parents were first cousins).

CasePMIDs: N/A

PMID: 25359263

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

PMID: 15207259

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

Case#: Savukoski_Fin_Major_Patient_1, no demographic details, Finnish origin

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing relied on linkage analysis using PCR-amplifiable polymorphisms, including microsatellite markers. The marker D13S160 was found to co-segregate with disease with a LOD score of 4.78 across 14 Finnish pedigrees, mapping the disease locus to chromosome 13q21.1-q32 (PMID:7942847). A follow-up study used two additional microsatellite markers to map the locus to a 200-kb region (PMID:8661106), which was then analyzed in the present study and found to contain a single coding gene.

CaseMethod1: Linkage analysis using PCR-amplifiable polymorphisms, including microsatellite markers, followed by more detailed linkage analysis using two additional microsatellite markers to map the locus to a smaller 200-kb region (PMID:8661106).

CaseMethod2: N/A

CaseGenotypingMethod: PCR products from the four exons of CLN5 were generated from the affected individual and a control individual and subjected to Sanger sequencing. Genome-wide analysis methods were not used.

Variant: Patient is homozygous for NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer), although this variant is referred to in the article as (AT)2467del.

ClinVar: 2564

gnomAD: The variant is reported to have a maximum allele frequency of 0.0008137 (in the European Finnish population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77575052-CAT-C

VariantEvidence: This frameshift variant is expected to truncate 16 amino acids from the C-terminus of CLN5 (between 4-5% of the total polypeptide), without triggering NMD. However, it abolishes an N-glycosylation site (PMID:24058541). This may explain why it fails to localize to large endosomes but rather is retained within the ER, possibly indicating improper folding (PMID:24058541). It also exhibits reduced stability relative to other variants (PMID:24058541).

CaseAddInfo: N/A

CasePMIDs: PMID:7942847, PMID:8661106

Case#: Savukoski_European_Patient_1, no demographic details, Dutch origin

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: PCR products from the four exons of CLN5 were generated from the affected individual and a control individual and subjected to Sanger sequencing. Genome-wide analysis methods were not used.

Variant: Patient is homozygous for NM_006493.4(CLN5):c.688G>A (p.Asp230Asn), although this variant is referred to in the article as c.G2127A or p.Asp279Asn.

ClinVar: 2566

gnomAD: The variant is reported to have a maximum allele frequency of 0.00005437 (in the East Asian population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77574715-G-A

VariantEvidence: This missense variant in the fourth / final exon is predicted to introduce an additional N-glycosylation site within the C-terminal region of CLN5. Slower electrophoretic migration of the exogenously expressed protein indicates that the abnormal N-glycosylation site is functional (PMID:20052765). The variant also disturbs lysosomal trafficking (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

PMID: 9662406

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

Case#: Savukoski_Fin_Minor_Patient_1, no demographic details, Finnish origin

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing relied on linkage analysis using PCR-amplifiable polymorphisms, including microsatellite markers. The marker D13S160 was found to co-segregate with disease with a LOD score of 4.78 across 14 Finnish pedigrees, mapping the disease locus to chromosome 13q21.1-q32 (PMID:7942847). A follow-up study used two additional microsatellite markers to map the locus to a 200-kb region (PMID:8661106), which was then analyzed in the present study and found to contain a single coding gene.

CaseMethod1: Linkage analysis using PCR-amplifiable polymorphisms, including microsatellite markers, followed by more detailed linkage analysis using two additional microsatellite markers to map the locus to a smaller 200-kb region (PMID:8661106).

CaseMethod2: N/A

CaseGenotypingMethod: PCR products from the four exons of CLN5 were generated from the affected individual and a control individual and subjected to Sanger sequencing. Genome-wide analysis methods were not used.

Variant: Patient is homozygous for NM_006493.4(CLN5):c.78G>A (p.Trp26Ter), although this variant is referred to in the article as c.G1517A or p.Trp75Stop.

ClinVar: 2565

gnomAD: The variant is reported to have a maximum allele frequency of 0.00005132 (in the European non-Finnish population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77566311-G-A

VariantEvidence: This nonsense variant is predicted to introduce a stop codon near the N-terminus of the encoded protein, likely triggering NMD and the absence of a protein product (loss of function).

CaseAddInfo: N/A

CasePMIDs: PMID:7942847, PMID:8661106

PMID: 23160995

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

ExperimentName: Genotyping of 4 Australian Cattle Dogs affected with NCL

NonHumanModel: Canis familiaris

GeneAlteration: While the model does not have an engineered gene alteration, all four affected animals are homozygous for the CLN5:c.619C>T variant. The unaffected parents of a fifth affected dog were both heterozygotes for this variant.

ModelPhenotype: HP:0001250 (Seizure), HP:0000572 (Visual loss), HP:0000708 (Behavioral abnormality), HP:0002370 (Poor coordination), HP:0002312 (Clumsiness), HP:0001251 (Ataxia), HP:0100299 (Muscle fiber inclusion bodies), HP:0002283 (Global brain atrophy), HP:0002119 (Ventriculomegaly), Note: inclusion bodies are membrane-associated and autofluorescent. Onset of phenotypes was between 12-18 months, and the condition was rapidly progressive, with euthanasia occurring between 20-27 months of age.

HumanPhenotype: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0100952 (Enlarged sylvian cistern), HP:0002059 (Cerebral atrophy), HP:0001272 (Cerebellar atrophy)

ModelEvidence: The model phenotypes closely match the human patient phenotypes in the timing of onset and rapid progression (Table 3), neurological details, vision problems, loss of coordination, and microscopic accumulation of storage/inclusion bodies (Figure 4, Figure 5).

ModelVariant: CLN5:c.619C>T p.Gln207Ter

PMID: 27203721

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

GroupName: Lebrun_2009_Group_1

GroupPresentingHPOs: HP:0001251 (Ataxia), HP:0001250 (Seizure), HP:0002463 (Language impairment), HP:0011463 (Childhood onset)

GroupNotHPOs: N/A

NumberMales: 3

NumberFemales: 1

CountryOrigin: One family is from the United Kingdom, while the other family's country of origin is not mentioned

Ethnicity: One family is of Pakistani ethnic origin, while the second family is of Afghan ethnic origin

Race: Not clearly described, but both families have origins within a similar region of Asia.

AgeRange: Onset occurred between the ages of 2 and 5

TotalNumber: 4

FamilyInfo: 4

NoFamily: 0

VariantCount: 4

NonVariant: 0

OtherVariant: 0

GroupPreviousTesting: Genome-wide methods were not initially used, as clinical phenotypes were consistent with diagnosis of neuronal ceroid lipofuscinosis (NCL). Enzymatic tests ruled out defects in the CLN1, CLN2, and CLN10 loci, while CLN3, CLN6, and CLN8 defects were ruled out by Sanger sequencing of the coding regions. SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely locus to harbor the causative variant.

GroupMethod1: SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely candidate for further genotyping.

GroupMethod2: N/A

GroupGenotypingMethod: CLN5 mRNA was reverse transcribed, PCR-amplified, and subjected to Sanger sequencing.

GroupAddInfo: N/A

Case#: Lebrun_2009_Patient_2, male, age 2-3 at onset, age 15 at death, family ethnicity reported as Afghan

CasePresentingHPOs: HP:0001251 (Ataxia), HP:0002474 (Expressive language delay), HP:0001250 (Seizure), HP:0011463 (Childhood onset), HP:0011421 (Death in adolescence)

CaseHPOFreeText: Onset was at age 2-3, with the first presenting phenotypes being ataxia and delay in speech development. Seizures began at age 4. Death occurred at age 15.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The extent of previous testing within this patient is unclear.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: CLN5 mRNA was reverse transcribed, PCR-amplified, and subjected to Sanger sequencing. This process was performed for both affected and control individuals (parents).

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.990G>T (p.Trp330Cys) variant, (although this variant is referred to in the article as c.1137G>T (p.Trp379Cys)).

ClinVar: 56530

gnomAD: The variant is reported to have a maximum allele frequency of 0.00006484 (in the European non-Finnish population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77575017-G-T

VariantEvidence: The missense variant introduces an additional cysteine into the protein product, potentially disrupting folding and three-dimensional structure. Immunofluorescent detection of the exogenously expressed variant in COS7 cells shows aberrant localization to the ER in contrast to the wild-type localization to the lysosome (Figure 3).

CaseAddInfo: The patient's family is consanguineous, as parents are described as first degree cousins. Parents were heterozygous for the variant. Family relationships between individuals were verified.

CasePMIDs: N/A

Case#: Lebrun_2009_Patient_1, male, age 5 at onset, U.K. origin with family ethnicity reported as Pakistani

CasePresentingHPOs: HP:0007010 (Poor fine motor coordination), HP:0007015 (Poor gross motor coordination), HP:0100952 (Enlarged sylvian cistern), HP:0001251 (Ataxia), HP:0001250 (Seizure), HP:0002465 (Poor speech), HP:0007064 (Progressive language deterioration), HP:0011463 (Childhood onset), HP:0000572 (Visual loss), HP:0030511 (Bradyopsia), HP:0000550 (Undetectable electroretinogram), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0002120 (Cerebral cortical atrophy), HP:0001272 (Cerebellar atrophy)

CaseHPOFreeText: Onset was at age 5, with the first presenting phenotypes being motor problems. Marked cerebellar sulcal widening with subarachnoidal space expansion was seen by brain MRI at age 5. Ataxia and language degradation were observed at age 6. Cortical and cerebellar atrophy presented by brain MRI scan at age 7. Visual problems presented at age 7.5, specifically with inability to focus on moving objects. Seizures first presented at age 8.5, along with bilaterally extinguished ERG. Skin biopsy showed fingerprint-type intralysosomal inclusions.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide methods were not initially used, as clinical phenotypes were consistent with diagnosis of neuronal ceroid lipofuscinosis (NCL). Enzymatic tests ruled out defects in the CLN1, CLN2, and CLN10 loci, while CLN3, CLN6, and CLN8 defects were ruled out by Sanger sequencing of the coding regions. SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely locus to harbor the causative variant.

CaseMethod1: SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely candidate for further genotyping.

CaseMethod2: N/A

CaseGenotypingMethod: CLN5 mRNA was reverse transcribed, PCR-amplified, and subjected to Sanger sequencing. This process was performed for both affected and control individuals (parents and unaffected sibling).

Variant: Patient is homozygous for NM_006493.4(CLN5):c.924_925del (p.Leu309fs), (although this variant is referred to in the article as c.1072_1073delTT (p.Leu358AlafsX4)).

ClinVar: 56526

gnomAD: The variant is reported to have a maximum allele frequency of 0.0002603 (in the Latino / Admixed American population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77574801-AAT-A

VariantEvidence: The frameshift variant results in premature truncation and disrupts approximately 14% of the protein product at the C-terminus. Immunofluorescent detection of the exogenously expressed variant in COS7 cells shows aberrant localization to the ER in contrast to the wild-type localization to the lysosome (Figure 3).

CaseAddInfo: The patient's family has some degree of consanguinity, as parents are described as distantly related. Parents were heterozygous for the variant. Family relationships between individuals were verified.

CasePMIDs: N/A

FamilyLabel: Lebrun_2009_Family_2

Family#PresentingHPOs: HP:0001251 (Ataxia), HP:0001250 (Seizure), HP:0000750 (Delayed speech and language development), HP:0011463 (Childhood onset),

Family#PresentingHPOFreeText: Ataxia and delay in speech development were the first presenting phenotypes, with onset between ages 2 and 3. Epileptic seizures first occurred at age 4.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: N/A

Ethnicity: Family is of Afghan ethnic origin.

Race: N/A

Family#PreviousTesting: The extent of previous testing within this family is unclear.

Family#Method1: N/A

Family#Method2: N/A

Family#GenotypingMethod: CLN5 mRNA was reverse transcribed, PCR-amplified, and subjected to Sanger sequencing. This process was performed for both affected and control individuals (parents).

Affected: 2

Unaffected: 2

Segregations: 1 segregation is reported in the family.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Lebrun_2009_Patient_2

Variant: Both affected patients are homozygous for the NM_006493.4(CLN5):c.990G>T (p.Trp330Cys) variant, (although this variant is referred to in the article as c.1137G>T (p.Trp379Cys)).

ClinVar: 56530

gnomAD: The variant is reported to have a maximum allele frequency of 0.00006484 (in the European non-Finnish population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77575017-G-T

FamilyAddInfo: The family is consanguineous, as parents are described as first degree cousins. Parents were heterozygous for the variant. Family relationships between individuals were verified.

FamilyPMIDs: N/A

PMID: 19309691

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

FamilyLabel: Lebrun_2009_Family_1

Family#PresentingHPOs: HP:0001251 (Ataxia), HP:0001250 (Seizure), HP:0002463 (Language impairment), HP:0011463 (Childhood onset),

Family#PresentingHPOFreeText: Abnormalities on brain MRI scan

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: United Kingdom

Ethnicity: Family is of Pakistani ethnic origin.

Race: N/A

Family#PreviousTesting: Genome-wide methods were not initially used, as clinical phenotypes were consistent with diagnosis of neuronal ceroid lipofuscinosis (NCL). Enzymatic tests ruled out defects in the CLN1, CLN2, and CLN10 loci, while CLN3, CLN6, and CLN8 defects were ruled out by Sanger sequencing of the coding regions. SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely locus to harbor the causative variant.

Family#Method1: SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely candidate for further genotyping.

Family#Method2: N/A

Family#GenotypingMethod: CLN5 mRNA was reverse transcribed, PCR-amplified, and subjected to Sanger sequencing. This process was performed for both affected and control individuals (parents and unaffected sibling).

Affected: 2

Unaffected: 1

Segregations: 1 segregation is reported in the family.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Lebrun_2009_Patient_1

Variant: Both affected patients are homozygous for NM_006493.4(CLN5):c.924_925del (p.Leu309fs), (although this variant is referred to in the article as c.1072_1073delTT (p.Leu358AlafsX4)).

ClinVar: 56526

gnomAD: The variant is reported to have a maximum allele frequency of 0.0002603 (in the Latino / Admixed American population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77574801-AAT-A

FamilyAddInfo: The family has some degree of consanguinity, as parents are described as distantly related. Parents were heterozygous for the variant. Family relationships between individuals were verified.

FamilyPMIDs: N/A

PMID: 20052765

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

FamilyLabel: Pineda-Trujillo_Family_1

Family#PresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003621 (Juvenile onset), HP:0000572 (Visual loss), HP:0003678 (Rapidly progressive), HP:0025406 (Asthenia), HP:0200085 (Limb tremor), HP:0000618 (Blindness), HP:0002540 (Inability to walk), HP:0000708 (Behavioral abnormality), HP:0007064 (Progressive language deterioration), HP:0001336 (Myoclonus), HP:0001250 (Seizure), HP:0002120 (Cerebral cortical atrophy), HP:0001272 (Cerebellar atrophy), HP:0002392 (EEG with polyspike wave complexes)

FamilyHPOFreeText: Onset was at age 9 in all family members, with the first presenting phenotype being visual failure rather than mental retardation (as reported elsewhere). Electron microscopy of skin biopsies found inclusions consisting of fingerprint profiles, which were often condensed and sometimes associated with lipid droplets. Tremor was observed in lower limbs. Blindness and inability to walk developed at approximately age 10 (within a year of symptom onset). Behavioral changes, gradual loss of language, myoclonus, and seizures all occurred within months of onset. Seizures were poorly responsive to valproate or clonazepam. Generalized cortical and cerebellar atrophy without signal intensity changes were seen by NMR at CT scans at ages 10-12. EEG specifically showed a generalized pattern of high-voltage polyspike–slow waves.

FamilyNotHPOs: HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003226 (Rectilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0001922 (Vacuolated lymphocytes), HP:0003457 (EMG abnormality), HP:0100285 (EMG: impaired neuromuscular transmission)

FamilyNotHPOFreeText: N/A

CountryOrigin: Colombia

Ethnicity: Family is reported to have mixed Spanish, Native American, and African ancestry, but no documented northern European ancestry.

Race: Admixture, combining Spanish, Native American, and African ancestry.

Family#PreviousTesting: Previous testing relied on clinical testing to establish neuronal ceroid lipofuscinosis (CLN), then used 10 different microsatellite markers to evaluate the 6 loci known at the time to be associated with CLN. (Note: This list of CLN-associated loci has since expanded from 6 to 8-12 genes.) The pedigree indicates consistent segregation of the disease phenotype with biallelic inheritance of the three markers in the CLN5 locus. CLN genes were then PCR-amplified and subjected to Sanger sequencing, identifying a variant in CLN5. CLN5 PCR products were additionally subjected to PshAI endonuclease digestion, as the variant abolishes a restriction site. Genome-wide analysis methods were not used.

Family#Method1: Linkage analysis with 10 microsatellite markers across 6 candidate loci known to be associated with CLN phenotypes.

Family#Method2: CLN genes (specifically CLN3 and CLN5) were PCR-amplified and subjected to Sanger sequencing, identifying a variant in CLN5.

Family#GenotypingMethod: CLN5 PCR products were subjected to PshAI endonuclease digestion, as the variant abolishes a restriction site. Genome-wide analysis methods were not used.

Affected: 2

Unaffected: 9

Segregations: 1 segregation is reported in the pedigree from Figure 1, with no individuals inconsistent with an autosomal recessive mode of inheritance. The family in question reportedly has multiple consanguinity loops.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Pineda-Trujillo_Patient_NCL-22

Variant: Both affected patients are homozygous for NM_006493.4(CLN5):c.188G>A (p.Arg63His), (although this variant is referred to in the article as c.1627G>A or p.Arg112His).

ClinVar: 2567

gnomAD: The variant is reported to have a maximum allele frequency of 0.00003274 (in the South Asian population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77569212-G-A

FamilyAddInfo: N/A

FamilyPMIDs: N/A

PMID: 15728307

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

Case#: Pineda-Trujillo_Patient_NCL-22, male, age 9 at onset and age 14 at death, Colombian origin with family ethnicity reported as an admixture of Spanish, Native American, and African ancestry

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003621 (Juvenile onset), HP:0000572 (Visual loss), HP:0003678 (Rapidly progressive), HP:0011421 (Death in adolescence), HP:0025406 (Asthenia), HP:0200085 (Limb tremor), HP:0000618 (Blindness), HP:0002540 (Inability to walk), HP:0000708 (Behavioral abnormality), HP:0007064 (Progressive language deterioration), HP:0001336 (Myoclonus), HP:0001250 (Seizure), HP:0002120 (Cerebral cortical atrophy), HP:0001272 (Cerebellar atrophy), HP:0002392 (EEG with polyspike wave complexes)

CaseHPOFreeText: Onset was at age 9, with the first presenting phenotype being visual failure rather than mental retardation. Electron microscopy of skin biopsies found inclusions consisting of fingerprint profiles, which were often condensed and sometimes associated with lipid droplets. Tremor was observed in lower limbs. Blindness and inability to walk developed at approximately age 10 (within a year of symptom onset). Behavioral changes, gradual loss of language, myoclonus, and seizures all occurred within months of onset. Seizures were poorly responsive to valproate or clonazepam. Generalized cortical and cerebellar atrophy without signal intensity changes were seen by NMR at CT scans at age 12. EEG specifically showed a generalized pattern of high-voltage polyspike–slow waves. Patient died at age 14.

CaseNotHPOs: HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003226 (Rectilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0001922 (Vacuolated lymphocytes), HP:0003457 (EMG abnormality), HP:0100285 (EMG: impaired neuromuscular transmission)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing relied on clinical testing to establish neuronal ceroid lipofuscinosis (CLN), then used 10 different microsatellite markers to evaluate the 6 loci known at the time to be associated with CLN. (Note: This list of CLN-associated loci has since expanded from 6 to 8-12 genes.) The pedigree indicates consistent segregation of the disease phenotype with biallelic inheritance of the three markers in the CLN5 locus. CLN genes were then PCR-amplified and subjected to Sanger sequencing, identifying a variant in CLN5. Genome-wide analysis methods were not used.

CaseMethod1: Linkage analysis with 10 microsatellite markers across 6 candidate loci known to be associated with CLN phenotypes.

CaseMethod2: CLN genes (specifically CLN3 and CLN5) were PCR-amplified and subjected to Sanger sequencing, identifying a variant in CLN5.

CaseGenotypingMethod: CLN5 PCR products were subjected to PshAI endonuclease digestion, as the variant abolishes a restriction site. Genome-wide analysis methods were not used.

Variant: Patient was homozygous for NM_006493.4(CLN5):c.188G>A (p.Arg63His), (although this variant is referred to in the article as c.1627G>A or p.Arg112His).

ClinVar: 2567

gnomAD: The variant is reported to have a maximum allele frequency of 0.00003274 (in the South Asian population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77569212-G-A

VariantEvidence: The variant encodes a missense substitution, and exhibits defective localization to the ER rather than the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

ExperimentName: Defective lysosomal sorting receptor degradation in CLN5-depleted HeLa cells

NonPatientCell: HeLa cells (EFO:0001185)

GeneFunction: Lysosomal organization (GO:0007040)

GeneAlteration: CLN5 (or the CLN1 control) was depleted by transient transfection of small interfering RNA (siRNA) into HeLa cells, 48 hrs. before assays were performed.

FunctionalEvidence: CLN5-depleted cells have reduced immunofluorescent signal (Fig. 2K) and reduced expression (Fig. 3A) of two lysosomal sorting receptors; cation-independent mannose 6-phosphate receptor (CI-MPR) and sortilin (Fig. 2K). CLN5-depleted cells also have fragmented TGN46 signal (Fig. 2Q) and increased precursor and intermediate forms of the lysosomal cargo protein cathepsin D (Fig. 3C). These findings are consistent with CI-MPR and sortilin failing to correctly recycle to the Golgi and being degraded in lysosomes instead, possibly due to a defect in a complex called retromer, which returns membrane-associated proteins from the endosome to the Golgi or other cellular compartments. Endosomal signal for the retromer subunit Vps26 is also decreased (Fig. 4E), and both Vps26 and Vps35 are increasingly cytosolic rather than membrane-bound in CLN5-depleted cells (Fig. 6A). These defects are reversed by exogenously expressing CLN5 (Fig. 7B). Rab7 recruitment to the endosome is also defective in CLN5-depleted cells (Figs. 8B,8M). Considering that CLN5 interacts with Rab5 and Rab7 (Fig. 9A), it may serve as a scaffold recruiting Rab7 and the retromer complex to the endosomal membrane, for the purpose of recycling membrane-associated receptors such as sortilin and CI-MPR out of the endosome. Thus, patients with CLN5 loss-of-function variants may have defective recruitment of the retromer complex to the lysosome / endosome and disordered trafficking of membrane proteins out of these compartments as a result.

FAVariants: N/A

PMID: 22431521

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

PMID: 15459177

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

ExperimentName: Mouse model of homozygous Cln5 loss

NonHumanModel: Mus musculus

GeneAlteration: Mice are homozygous for Cln5 loss of function, caused by Insertion of a neomycin resistance cassette eliminating exon 3, resulting in a premature stop codon in exon 4. The presence or absence of a truncated gene product was not assessed.

ModelPhenotype: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0000572 (Visual loss)

HumanPhenotype: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0000572 (Visual loss)

ModelEvidence: The model phenotypes closely match the human patient phenotypes at the microscopic level (characteristic autofluorescent inclusion bodies ) as well as the loss of vision, but do not reproduce neurological features such as seizures, ataxia, loss of motor coordination, mental regression, and behavioral changes.

ModelVariant: While it is unclear whether the mice express a truncated form of Cln5 or whether this form is degraded, the predicted protein product does not represent a particular human variant. The authors speculate that it may be most similar to the NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variant (PMID:10953198).