CaseKLC2: Male, 32 yrs death, Japan, Asian

CasePresentingHPOs: HP:0001249, HP:0002078, HP:0000651, HP:0008353, HP:0000992 (Intellectual disability, Truncal ataxia, Diplopia, Neutral hyperaminoaciduria, Cutaneous photosensitivity)

HPOsFreeText: Monoamino-monocarboxylic aciduria

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are first-cousin consanguineous, Max LOD score is 2.1 for family

CasePreviousTesting: Defects in the intestinal absorption of monoamino-monocarboxylic acids determined by oral loading; Urine analyses confirmed the absence of hyperaminoaciduria in the mother (III-4), father (III-5) and the younger brother (IV-3), Brother of proband

CaseGenotypingMethod: DNA was isolated from peripheral blood samples and from liver samples collected at autopsy. A genome-wide screen with 343 different markers was carried out and linkage analysis performed using homozygosity mapping. Both SLC6A18 and SLC6A19 were investigated for possible pathogenicity, with SLC6A19's pattern of expression supporting it as a primary candidate. Intronic primers were used to bidirectionally sequence each exon and flanking intronic regions, locating a homozygous frameshift mutation that perfectly segregated with the phenotype.

CasePMIDs: 2582682, 11394870

Variant: NM_001003841.3(SLC6A19):c.882_883TG1

ClinVar: 2018 https://ww.ncbi.nlm.nih.gov/clinvar/variation/2018/

gnomAD: 0.000008900, https://gnomad.broadinstitute.org/variant/5-1214174-CTG-C?dataset=gnomad_r2_1

FamilyHA: White, Great Britian

FamilyPresentingHPOs: HP:0000988, HP:0002344, HP:0002359, HP:0002355, HP:0007210, HP:0000712, HP:0002066, HP:0000639, HP:0001347, HP:0008353 (Skin rash, Progressive neurologic deterioration, Frequent falls, Difficulty walking, Lower limb amyotrophy, Emotional lability, Gait ataxia, Nystagmus, Hyperreflexia, Neutral hyperaminoaciduria)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Homozygosity mapping and fine mapping in ten members of two consanguineous families (the siblings in whom Hartnup disorder was originally discovered; family A) and in siblings from the US revealed linkage of Hartnup disorder to 5p15 only in family A, with a maximum combined multipoint lod score of 2.31 at 11.24 cM. This confirmed a previous study showing linkage to the same region. Both SLC6A18 and SLC6A19 were investigated for possible pathogenicity, with SLC6A19's pattern of expression supporting it as a primary candidate. Intronic primers were used to bidirectionally sequence each exon and flanking intronic regions, locating a homozygous splice site mutation that perfectly segregated with the phenotype.

FamilyPreviousTesting: Consistent testing showed the consistent phenotypes were the hyperaminoaciduria among all family members; Linkage analysis for SLC3A2, SLC7A8, SLC1A5, SLC6A18, and SLC6A20 were all negative for amy correlation

FamilyAddInfo:

FamilyProband: Case EHAA

FamilyPMIDs: 13358233

Variant: NM_001003841.3(SLC6A19):c.1173+2T>G

ClinVar: 449553 https://www.ncbi.nlm.nih.gov/clinvar/variation/449553/

gnomAD: 0.00008019, https://gnomad.broadinstitute.org/variant/5-1217062-T-C?dataset=gnomad_r2_1

Affected: 4

Unaffected: 5

pLOD: 2.31 at 11.24 cM

AddSegregationInfo: Family is consanguineous (first cousins), Candidate gene sequencing, Pedigree in Figure 1aA

CaseKLE: Male, Japan, Asian

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText:

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePreviousTesting: Identified via neonatal mass screening

CaseGenotypingMethod: Both SLC6A18 and SLC6A19 were investigated for possible pathogenicity, with SLC6A19's pattern of expression supporting it as a primary candidate. Intronic primers were used to bidirectionally sequence each exon and flanking intronic regions, locating two compound heterozygous mutations that perfectly segregate with the phenotype.

Variant1: NM_001003841.3:c.340del (L114fs*114)

CAID: CA916079859 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA916079859

gnomAD: Not in gnomAD

Variant2: NM_001003841.3:c.682_683delinsTA (p.Thr228Ter)

CAID: CA916079860 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA916079860

gnomAD: Not in gnomAD

CaseKLC: Male, 42 yrs death, Japan, Asian

CasePresentingHPOs: HP:0001394, HP:0002078, HP:0000651, HP:0008353, HP:0003763, HP:0100785, HP:0001276, HP:0030904, HP:0030906, HP:0030903 (Cirrhosis, Truncal ataxia, Diplopia, Neutral hyperaminoaciduria, Bruxism, Insomnia, Hypertonia, Glabellar reflex, Suck reflex, Grasp reflex)

HPOsFreeText: Monoamino-monocarboxylic aciduria, Transient stupor

CaseNotHPOs: HP:0000992, HP:0011123, HP:0040129 (Cutaneous photosensitivity, Dermatitis, Abnormal nerve conduction velocity)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are first-cousin consanguineous, Max LOD score is 2.1 for family

CasePreviousTesting: Defects in the intestinal absorption of monoamino-monocarboxylic acids determined by oral loading; Urine analyses confirmed the absence of hyperaminoaciduria in the mother (III-4), father (III-5) and the younger brother (IV-3);

CaseGenotypingMethod: DNA was isolated from peripheral blood samples and from liver samples collected at autopsy. A genome-wide screen with 343 different markers was carried out and linkage analysis performed using homozygosity mapping. Both SLC6A18 and SLC6A19 were investigated for possible pathogenicity, with SLC6A19's pattern of expression supporting it as a primary candidate. Intronic primers were used to bidirectionally sequence each exon and flanking intronic regions, locating a homozygous frameshift mutation that perfectly segregated with the phenotype.

CasePMIDs: 2582682, 11394870

Variant: NM_001003841.3(SLC6A19):c.882_883TG[1] (p.Val295fs)

ClinVar: 2018 https://ww.ncbi.nlm.nih.gov/clinvar/variation/2018/

gnomAD: 0.000008900, https://gnomad.broadinstitute.org/variant/5-1214174-CTG-C?dataset=gnomad_r2_1

CaseKLD: Female, 6 yrs report, Japan, Asian

CasePresentingHPOs: HP:0001047, HP:0002028, HP:0004325, HP:0004322, HP:0008353, HP:0001397, HP:0001249 (Atopic dermatitis, Chronic diarrhea, Decreased body weight, Short stature, Neutral hyperaminoaciduria, Hepatic steatosis, Intellectual disability)

HPOsFreeText: Lowered concentrations of valine, methionine, isoleucine, tyrosine, phenylalanine, and tryptophan with generalized mild hypoaminoacidemia

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are first-cousin consanguineous, Max LOD score is 1.45 for family, Pedigree in Figure 1aD

CasePreviousTesting: Oral loading tests demonstrated impaired absorption of tryptophan from the gut, while the absorption of proline was intact; Absence of hyperaminoaciduria was confirmed by urine analyses of the pedigree members

CaseGenotypingMethod: DNA was isolated from peripheral blood samples and from liver samples collected at autopsy. A genome-wide screen with 343 different markers was carried out and linkage analysis performed using homozygosity mapping. Both SLC6A18 and SLC6A19 were investigated for possible pathogenicity, with SLC6A19's pattern of expression supporting it as a primary candidate. Intronic primers were used to bidirectionally sequence each exon and flanking intronic regions, locating a homozygous missense mutation that perfectly segregated with the phenotype.

CasePMIDs: 2582682, 11394870

Variant: NM_001003841.3:c.169C>T (p.Arg57Cys)

CAID: CA3182581 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3182581

gnomAD: 0.0002181, https://gnomad.broadinstitute.org/variant/5-1201934-C-T

CaseAHN3.4: Australia, White

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variants segregate with the disease

CasePMIDs: 15286788

CasePreviousTesting: Hartnup aminoaciduria profile was confirmed by ion exchange high performance liquid chromatography

CaseGenotypingMethod: All SLC6A19 exons and flanking introns were directly amplified and sequenced from genomic DNA.

Variant1: NM_001003841.3:c.719G>A (p.Arg240Gln)

CAID: CA3182844, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3182844

gnomAD: 0.0001307, https://gnomad.broadinstitute.org/variant/5-1213633-G-A

Variant2: NM_001003841.3(SLC6A19):c.1701+1G>A

ClinVar: 623442, https://www.ncbi.nlm.nih.gov/clinvar/variation/623442/

gnomAD: 0.00005286, https://gnomad.broadinstitute.org/variant/5-1221429-G-A

CaseAHN5.1: Australia, White

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variant 1 is in-trans with Variants 2 and 3, which are in cis; Variant segregates with the disease

CasePMIDs: 17555458

CasePreviousTesting: Hartnup aminoaciduria profile was confirmed by ion exchange high performance liquid chromatography;

CaseGenotypingMethod: All SLC6A19 exons and flanking introns were directly amplified and sequenced from genomic DNA.

Variant1: NM_001003841.3:c.196G>A (p.Gly66Arg)

CAID: CA359061114 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA359061114

gnomAD: Not in gnomAD

Variant2: NM_001003841.3(SLC6A19):c.517G>A (p.Asp173Asn)

ClinVar: 2019 https://www.ncbi.nlm.nih.gov/clinvar/variation/2019/

gnomAD: 0.003016, https://gnomad.broadinstitute.org/variant/5-1212453-G-A

Variant3: NM_001003841.3(SLC6A19):c.718C>T (p.Arg240Ter)

ClinVar: 2020 https://www.ncbi.nlm.nih.gov/clinvar/variation/2020/

gnomAD: 0.0001960, https://gnomad.broadinstitute.org/variant/5-1213632-C-T

CaseAHN9.2: Australia, White

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variants segregate with the disease

CasePreviousTesting: Hartnup aminoaciduria profile was confirmed by ion exchange high performance liquid chromatography;

CaseGenotypingMethod: All SLC6A19 exons and flanking introns were directly amplified and sequenced from genomic DNA.

Variant1: NM_001003841.3(SLC6A19):c.517G>A (p.Asp173Asn)

ClinVar: 2019 https://www.ncbi.nlm.nih.gov/clinvar/variation/2019/

gnomAD: 0.003016, https://gnomad.broadinstitute.org/variant/5-1212453-G-A

Variant2: NM_001003841.3:c.1550A>G (p.Asp517Gly)

CAID: CA3183226, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3183226

gnomAD: 0.00004675, https://gnomad.broadinstitute.org/variant/5-1221277-A-G

CaseCHN2.1: Canada, White

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variants segregate with the disease

CasePreviousTesting: Hartnup aminoaciduria profile was confirmed by ion exchange high performance liquid chromatography

CaseGenotypingMethod: All SLC6A19 exons and flanking introns were directly amplified and sequenced from genomic DNA.

Variant1: NM_001003841.3:c.532C>T (p.Arg178Ter)

CAID: CA3182753, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3182753

gnomAD: 0.0004414, https://gnomad.broadinstitute.org/variant/5-1212468-C-T

Variant2: NM_001003841.3:c.1213G>A (p.Glu405Lys)

CAID: CA3183103, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3183103

gnomAD: 0.0001203, https://gnomad.broadinstitute.org/variant/5-1219057-G-A

CaseCHN1.1: Canada, White

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variants segregate with the disease, Has a sibling with the same variant and amino acid profile

CasePreviousTesting: Hartnup aminoaciduria profile was confirmed by ion exchange high performance liquid chromatography;

CaseGenotypingMethod: All SLC6A19 exons and flanking introns were directly amplified and sequenced from genomic DNA.

Variant1: NM_001003841.3:c.196G>A (p.Gly66Arg)

CAID: CA359061114 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA359061114

gnomAD: Not in gnomAD

Variant2: NM_001003841.3:c.982C>T (p.Arg328Cys)

CAID: CA3182972, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3182972

gnomAD: 0.0002479, https://gnomad.broadinstitute.org/variant/5-1216767-C-T

CaseAHN16.1: Australia, White

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variants segregate with the disease

CasePreviousTesting: Hartnup aminoaciduria profile was confirmed by ion exchange high performance liquid chromatography;

CaseGenotypingMethod: All SLC6A19 exons and flanking introns were directly amplified and sequenced from genomic DNA.

Variant1: NM_001003841.3:c.277G>A (p.Gly93Arg)

CAID: CA3182636 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3182636

gnomAD: 0.0001195, https://gnomad.broadinstitute.org/variant/5-1208935-G-A

Variant2: NM_001003841.3(SLC6A19):c.517G>A (p.Asp173Asn)

ClinVar: 2019 https://www.ncbi.nlm.nih.gov/clinvar/variation/2019/

gnomAD: 0.003016, https://gnomad.broadinstitute.org/variant/5-1212453-G-A

CaseB1: United States, White

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variants segregate with the disease, Has a brother (B2) also homozygous for variant and positive for amino acid profile

CasePreviousTesting: Hartnup aminoaciduria profile was confirmed by ion exchange high performance liquid chromatography;

CaseGenotypingMethod: All SLC6A19 exons and flanking introns were directly amplified and sequenced from genomic DNA.

Variant: NM_001003841.3(SLC6A19):c.517G>A (p.Asp173Asn)

ClinVar: 2019 https://www.ncbi.nlm.nih.gov/clinvar/variation/2019/

gnomAD: 0.003016, https://gnomad.broadinstitute.org/variant/5-1212453-G-A

CaseAHN8.1: Australia, White

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variants segregate with the disease

CasePreviousTesting: Hartnup aminoaciduria profile was confirmed by ion exchange high performance liquid chromatography;

CaseGenotypingMethod: All SLC6A19 exons and flanking introns were directly amplified and sequenced from genomic DNA.

Variant1: NM_001003841.3:c.277G>A (p.Gly93Arg)

CAID: CA3182636 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3182636

gnomAD: 0.0001195, https://gnomad.broadinstitute.org/variant/5-1208935-G-A

Variant2: NM_001003841.3(SLC6A19):c.1173+2T>G

ClinVar: 449553 https://www.ncbi.nlm.nih.gov/clinvar/variation/449553/

gnomAD: 0.0006791, https://gnomad.broadinstitute.org/variant/5-1217062-T-G

CaseAHN6.3: Australia, White

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variants segregate with the disease

CasePMIDs: 15286788

CasePreviousTesting: Hartnup aminoaciduria profile was confirmed by ion exchange high performance liquid chromatography;

CaseGenotypingMethod: All SLC6A19 exons and flanking introns were directly amplified and sequenced from genomic DNA.

Variant1: NM_001003841.3(SLC6A19):c.517G>A (p.Asp173Asn)

ClinVar: 2019 https://www.ncbi.nlm.nih.gov/clinvar/variation/2019/

gnomAD: 0.003016, https://gnomad.broadinstitute.org/variant/5-1212453-G-A

Variant2: NM_001003841.3:c.1550A>G (p.Asp517Gly)

CAID: CA3183226, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3183226

gnomAD: 0.00004675, https://gnomad.broadinstitute.org/variant/5-1221277-A-G

CaseAHN15.1: Australia, White

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variants segregate with the disease

CasePreviousTesting: Hartnup aminoaciduria profile was confirmed by ion exchange high performance liquid chromatography;

CaseGenotypingMethod: All SLC6A19 exons and flanking introns were directly amplified and sequenced from genomic DNA.

Variant1: NM_001003841.3(SLC6A19):c.517G>A (p.Asp173Asn)

ClinVar: 2019 https://www.ncbi.nlm.nih.gov/clinvar/variation/2019/

gnomAD: 0.003016, https://gnomad.broadinstitute.org/variant/5-1212453-G-A

Variant2: NM_001003841.3:c.850G>A (p.Gly284Arg)

CAID: CA3182918, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3182918

gnomAD: 0.00005440, https://gnomad.broadinstitute.org/variant/5-1214143-G-A

CaseSE4: Male, Australia

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseGenotypingMethod: Five loci were investigated for evidence of linkage to Hartnup due to their established role in amino acid transport including SLC3A2, SLC7A8, SLC1A5, SLC6A18, and SLC6A19. These 5 regions were studied with microsattelite markers and produced linkage only between D5S392 and D5S417, the region with SLC6A18 and 19. SLC6A18 did not increase neutral amino acid uptake in X. laevis oocytes so SLC6A19 was investigated and directly sequenced in the families each of which displayed a causal variant.

CasePreviousTesting: SLC1A5 had no causative variants detected.

CaseAddInfo: Asymptomatic except for hyperaminoaciduria

Variant: NM_001003841.3(SLC6A19):c.517G>A (p.Asp173Asn)

ClinVar: 2019 https://www.ncbi.nlm.nih.gov/clinvar/variation/2019/

gnomAD: 0.003016, https://gnomad.broadinstitute.org/variant/5-1212453-G-A?dataset=gnomad_r2_1

FamilySE1: Australia

FamilyPresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Five loci were investigated for evidence of linkage to Hartnup due to their established role in amino acid transport including SLC3A2, SLC7A8, SLC1A5, SLC6A18, and SLC6A19. These 5 regions were studied with microsattelite markers and produced linkage only between D5S392 and D5S417, the region with SLC6A18 and 19. SLC6A18 did not increase neutral amino acid uptake in X. laevis oocytes so SLC6A19 was investigated and directly sequenced in the families each of which displayed a causal variant.

FamilyPreviousTesting: SLC1A5 had no causative variants detected.

FamilyAddInfo: Family is asymptomatic except for hyperaminoaciduria

Variant1: NM_001003841.3(SLC6A19):c.1173+2T>G

ClinVar: 449553 https://www.ncbi.nlm.nih.gov/clinvar/variation/449553/

gnomAD: 0.00008019, https://gnomad.broadinstitute.org/variant/5-1217062-T-C?dataset=gnomad_r2_1

Variant2: NM_001003841.3:c.725T>C (p.Leu242Pro)

CAID: CA3182847 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3182847

gnomAD: 0.0001307, https://gnomad.broadinstitute.org/variant/5-1213639-T-C

Affected: 3

Unaffected: 3

pLOD: 2.68 combined max LOD score for linkage between D5S392 and D5S417

AddSegregationInfo: Pedigree in SuppFig1A, Candidate gene sequencing

CaseSE7: Female, Australia

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseGenotypingMethod: Five loci were investigated for evidence of linkage to Hartnup due to their established role in amino acid transport including SLC3A2, SLC7A8, SLC1A5, SLC6A18, and SLC6A19. These 5 regions were studied with microsattelite markers and produced linkage only between D5S392 and D5S417, the region with SLC6A18 and 19. SLC6A18 did not increase neutral amino acid uptake in X. laevis oocytes so SLC6A19 was investigated and directly sequenced in the families each of which displayed a causal variant.

CasePreviousTesting: SLC1A5 had no causative variants detected.

CaseAddInfo: Asymptomatic except for hyperaminoaciduria

Variant1: NM_001003841.3(SLC6A19):c.517G>A (p.Asp173Asn)

ClinVar: 2019 https://www.ncbi.nlm.nih.gov/clinvar/variation/2019/

gnomAD: 0.003016, https://gnomad.broadinstitute.org/variant/5-1212453-G-A?dataset=gnomad_r2_1

Variant2: NM_001003841.3(SLC6A19):c.718C>T (p.Arg240Ter)

ClinVar: 2020 https://www.ncbi.nlm.nih.gov/clinvar/variation/2020/

gnomAD: 0.0001960, https://gnomad.broadinstitute.org/variant/5-1213632-C-T

CaseSE5: Male, Australia

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseGenotypingMethod: Five loci were investigated for evidence of linkage to Hartnup due to their established role in amino acid transport including SLC3A2, SLC7A8, SLC1A5, SLC6A18, and SLC6A19. These 5 regions were studied with microsattelite markers and produced linkage only between D5S392 and D5S417, the region with SLC6A18 and 19. SLC6A18 did not increase neutral amino acid uptake in X. laevis oocytes so SLC6A19 was investigated and directly sequenced in the families each of which displayed a causal variant.

CasePreviousTesting: SLC1A5 had no causative variants detected.

CaseAddInfo: Asymptomatic except for hyperaminoaciduria

Variant1: NM_001003841.3(SLC6A19):c.517G>A (p.Asp173Asn)

ClinVar: 2019 https://www.ncbi.nlm.nih.gov/clinvar/variation/2019/

gnomAD: 0.003016, https://gnomad.broadinstitute.org/variant/5-1212453-G-A?dataset=gnomad_r2_1

Variant2: NM_001003841.3(SLC6A19):c.718C>T (p.Arg240Ter)

ClinVar: 2020 https://www.ncbi.nlm.nih.gov/clinvar/variation/2020/

gnomAD: 0.0001960, https://gnomad.broadinstitute.org/variant/5-1213632-C-T

FamilySE2: Australia

FamilyPresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Five loci were investigated for evidence of linkage to Hartnup due to their established role in amino acid transport including SLC3A2, SLC7A8, SLC1A5, SLC6A18, and SLC6A19. These 5 regions were studied with microsattelite markers and produced linkage only between D5S392 and D5S417, the region with SLC6A18 and 19. SLC6A18 did not increase neutral amino acid uptake in X. laevis oocytes so SLC6A19 was investigated and directly sequenced in the families each of which displayed a causal variant.

FamilyPreviousTesting: SLC1A5 had no causative variants detected.

FamilyAddInfo: Family is asymptomatic except for hyperaminoaciduria

Variant1: NM_001003841.3(SLC6A19):c.517G>A (p.Asp173Asn)

ClinVar: 2019 https://www.ncbi.nlm.nih.gov/clinvar/variation/2019/

gnomAD: 0.003016, https://gnomad.broadinstitute.org/variant/5-1212453-G-A?dataset=gnomad_r2_1

Variant2: NM_001003841.3:c.1501G>A (p.Glu501Lys)

CAID: CA359075496, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA359075496

gnomAD: 0.00006164, https://gnomad.broadinstitute.org/variant/5-1219742-G-A

Affected: 2

Unaffected: 3

pLOD: 2.68 combined max LOD score for linkage between D5S392 and D5S417

AddSegregationInfo: Pedigree in SuppFig1B, Candidate gene sequencing