Case6: Male, White

CasePresentingHPOs: HP:0012072, HP:0002194, HP:0002788, HP:0001256, HP:0000722, HP:0000750, HP:0002360, HP:0005487, HP:0002057, HP:0000664, HP:0000286, HP:0000494, HP:0000368, HP:0000322, HP:0009778, HP:0004209 (Aciduria, Delayed gross motor development, Recurrent upper respiratory tract infections, Mild intellectual disability, Obsessive-compulsive behavior, Delayed speech and language development, Sleep disturbance, Prominent metopic ridge, Prominent glabella, Synophrys, Epicanthus, Downslanted palpebral fissures, Low-set posteriorly rotated ears, Short philtrum, Short thumb, Clinodactyly of the 5th finger)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are non-consanguineous

CasePreviousTesting: Extensive metabolic screening revealed elevated urine AAA (618 mmol/mol creatinine; ref <49) and KAA (348 mmol/mol creatinine; ref not detected) as well as plasma AAA (53 umol/L; ref <12)

CaseGenotypingMethod: All 17 exons and flanking intronic sequences of DHTKD1 were Sanger sequenced.

Variant1: NM_018706.6:c.2185G>A (p.Arg455Gln)

CAID: CA5407838 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA5407838

gnomAD: 0.0002538, https://gnomad.broadinstitute.org/variant/10-12139688-G-A

Variant2: NM_018706.6:c.1159+5G>A

CAID: CA5407761 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA5407761

gnomAD: 0.0001170, https://gnomad.broadinstitute.org/variant/10-12133688-G-A

Case10: Male, Mixed, 6 yrs died

CasePresentingHPOs: HP:0002240, HP:0006579, HP:0003560, HP:0001263, HP:0002376 (Hepatomegaly, Prolonged neonatal jaundice, Muscular dystrophy, Global developmental delay, Developmental regression)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband is homozygous

CasePreviousTesting: Patient fibroblasts were analyzed for mutations in SLC25A21 and activities of KATII with no abnormalities; Niemann-Pick type C disease was diagnosed via bone marrow investigations; Metabolic screening suggested a defect in lysine metabolism with urine values of AAA and KAA increasing following a lysine challenge (200 mg/kg p.o.)

CaseGenotypingMethod: All 17 exons and flanking intronic sequences of DHTKD1 were Sanger sequenced.

Variant: NM_018706.6:c.700_701delinsGG (p.Leu234Gly)

CAID: CA915940679 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA915940679

gnomAD: Not in gnomAD

Case1: Male,

CasePresentingHPOs:

HPOsFreeText:

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePreviousTesting:

CaseGenotypingMethod:

Variant1: NM_018706.5(DHTKD1):c.2185G>A (p.Gly729Arg)

ClinVar: 39564 https://www.ncbi.nlm.nih.gov/clinvar/variation/39564/

gnomAD: 0.002748, https://gnomad.broadinstitute.org/variant/10-12154929-G-A

Variant2:

ClinVar:

gnomAD:

Case5: Male, 16 yrs report

CasePresentingHPOs: HP:0012072, HP:0010864, HP:0000734 (Aciduria, Severe intellectual disability, Disinhibition)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

CasePreviousTesting: Patient fibroblasts were analyzed for mutations in SLC25A21 and activities of KATII with no abnormalities; Metabolic work-up at 17 years of age revealed strongly elevated AAA (549 mmol/mol creatinine; ref <14) and KAA

CaseGenotypingMethod: All 17 exons and flanking intronic sequences of DHTKD1 were Sanger sequenced.

Variant1: NM_018706.6:c.2185G>A (p.Arg455Gln)

CAID: CA5407838 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA5407838

gnomAD: 0.0002538, https://gnomad.broadinstitute.org/variant/10-12139688-G-A

Variant2: NM_018706.6:c.2329T>C (p.Ser777Pro)

CAID: CA376014875 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA376014875

gnomAD: 0.000008948, https://gnomad.broadinstitute.org/variant/10-12159681-T-C

Case9: Male, Turkey, 24 yrs report,

CasePresentingHPOs: HP:0002251, HP:0001321, HP:0001161, HP:0025356, HP:0002474, HP:0000708, HP:0001488, HP:0002317, HP:0000646, HP:0000486 (Aganglionic megacolon, Cerebellar hypoplasia, Hand polydactyly, Psychomotor retardation, Expressive language delay, Behavioral abnormality, Bilateral ptosis, Unsteady gait, Strabismus)

HPOsFreeText: Dysgnathia

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband is homozygous, Parents are consanguineous, cDNA amplification of the exons 8 and 9 in this patient revealed an insertion of 64 base pairs due to the use of a cryptic donor site leading to a premature stop codon and a likely null allele; Proband has two healthy sisters

CasePreviousTesting: Patient fibroblasts were analyzed for mutations in SLC25A21 and activities of KATII with no abnormalities; A metabolic work-up revealed alpha-ketoadipic aciduria and alpha-aminoadipic aciduria; A non-verbal intelligence test yielded a slightly decreased value; A single metabolic decompensation in adulthood was ascribed to Helicobacter pylori and its eradication improved the patient’s well-being.

CaseGenotypingMethod: All 17 exons and flanking intronic sequences of DHTKD1 were Sanger sequenced.

Variant: NM_018706.6:c.1671+1G>A

CAID: CA5407905 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA5407905

gnomAD: 0.0001399, https://gnomad.broadinstitute.org/variant/10-12139996-G-A

Case8: Female

CasePresentingHPOs: HP:0001270, HP:0001252, HP:0011342, HP:0007479 (Motor delay, Muscular hypotonia, Mild motor developmental delay, Congenital nonbullous ichthyosiform erythroderma)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Consanguineity is suspected, Proband is homozygous

CasePreviousTesting: Patient fibroblasts were analyzed for mutations in SLC25A21 and activities of KATII with no abnormalities; Urine AAA and KAA were elevated. Oxidation of radiolabeled AAA in fibroblasts was deficient.

CaseGenotypingMethod: All 17 exons and flanking intronic sequences of DHTKD1 were Sanger sequenced.

CasePMIDs: 1112064, 1112065

Variant: NM_018706.7(DHTKD1):c.2134C>T (p.Arg712Ter)

ClinVar: 572241 https://www.ncbi.nlm.nih.gov/clinvar/variation/572241/

gnomAD: 0.00003267, https://gnomad.broadinstitute.org/variant/10-12149994-C-T

Case2: Male, White, 18 yrs report

CasePresentingHPOs: HP:0010864, HP:0000717, HP:0002019, HP:0002300, HP:0001250, HP:0012072 (Severe Intellectual disability, Autism, Constipation, Mutism, Seizures, Aciduria)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001627, HP:0000175 (Abnormal heart morphology, Cleft palate)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are non-consanguineous, Has 22q11.2 deletion so phenotypes other than urinary excretion may result from that

CasePreviousTesting: Urine analysis at 25 years of age showed an increase of AAA (226 mmol/mol creatinine; ref <14) and KAA (68 mmol/mol creatinine; ref not detected)

CaseGenotypingMethod: All 17 exons and flanking intronic sequences of DHTKD1 were Sanger sequenced. SSCP analysis confirmed the presence of the 22q11.2 deletion.

Variant1: NM_018706.5(DHTKD1):c.2185G>A (p.Gly729Arg)

ClinVar: 39564 https://www.ncbi.nlm.nih.gov/clinvar/variation/39564/

gnomAD: 0.002748, https://gnomad.broadinstitute.org/variant/10-12154929-G-A

Variant2: NM_018706.7(DHTKD1):c.2318C>T (p.Pro773Leu)

ClinVar: 420289 https://www.ncbi.nlm.nih.gov/clinvar/variation/420289/

gnomAD: 0.0001423, https://gnomad.broadinstitute.org/variant/10-12155062-C-T

Case3: Female, 5 yrs report

CasePresentingHPOs: HP:0012072 (Aciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

CasePreviousTesting: Partial biotinidase deficiency (19%) was confirmed; Urine AAA (552 mmol/mol creatinine; ref <91) and KAA (251 mmol/mol creatinine) were clearly increased. At 5 years of age, urine AAA and KAA as well as plasma AAA were persistently elevated.

CaseGenotypingMethod: All 17 exons and flanking intronic sequences of DHTKD1 were Sanger sequenced.

Variant1: NM_018706.5(DHTKD1):c.2185G>A (p.Gly729Arg)

ClinVar: 39564 https://www.ncbi.nlm.nih.gov/clinvar/variation/39564/

gnomAD: 0.002748, https://gnomad.broadinstitute.org/variant/10-12154929-G-A

Variant2: NM_018706.7(DHTKD1):c.1309G>T (p.Glu437Ter)

ClinVar: 574714 https://www.ncbi.nlm.nih.gov/clinvar/variation/574714/

gnomAD: 0.0001316, https://gnomad.broadinstitute.org/variant/10-12136221-G-T

Case1: Female

CasePresentingHPOs: HP:0011343, HP:0012072, HP:0007018 (Moderate global developmental delay, Aciduria, Attention deficit hyperactivity disorder)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are non-consanguineous, Unremarkable family history, Variants are parentally confirmed with c.2185 G>A apparently de novo

CasePreviousTesting: At 2 yrs had elevated 2-oxoadipate (range = 10–120 mmol/mol creatinine) and 2-hydroxyadipate (range = 5–40 mmol/mol creatinine) in urine (Reference 0 mmol/mol creatinine); Elevated 2-aminoadipate (120 μmol/l); Moderate protein restriction did not influence disease course and was discontinued, Serial cranial magnetic-resonance-imaging studies showed no morphological abnormalities; Neuropsychological testing at 8 years revealed an IQ of 117; Symptoms improved after implementation of methylphenidate and at 14 is clinically normal; No mutation detected in ODC

CaseGenotypingMethod: Whole exome sequencing was performed to identify mutations responsible for the biochemical abnormality. Exonic sequences were enriched and sequenced with data analysis being used to filter according to inheritance and low allele frequencies in controls. This narrowed down to eight different genes (ADAMTS10, AIRE, C8orf38, DHTKD1, OVOS2, CAMTA2, LPPR3, and RADIL) of which three had been associated with unrelated phenotypes and only one other had predicted pathogenic variants, DHTKD1.

Variant1: NM_018706.7(DHTKD1):c.1A>G (p.Met1Val)

ClinVar: 39563 https://www.ncbi.nlm.nih.gov/clinvar/variation/39563/

gnomAD: Not in gnomAD

Variant2: NM_018706.5(DHTKD1):c.2185G>A (p.Gly729Arg)

ClinVar: 39564 https://www.ncbi.nlm.nih.gov/clinvar/variation/39564/

gnomAD: 0.002748, https://gnomad.broadinstitute.org/variant/10-12154929-G-A

Case2: Female

CasePresentingHPOs: HP:0000252, HP:0001270, HP:0000750, HP:0001252 (Microcephaly, Motor delay, Delayed speech and language development, Muscular hypotonia)

HPOsFreeText: N/A

CaseNotHPOs: HP:0000407 (Sensorineural hearing impairment)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are non-consanguineous, Compound heterozyosity was confirmed in trans via parental testing

CasePreviousTesting: At 2 yrs levels were at 2-oxoadipate, 520–970 mmol/mol creatinine; 2-hydroxyadipate, 100–150 mmol/mol creatinine; 2-aminoadipate, elevated; Moderate protein restriction did not influence disease course; IQ of 87

CaseGenotypingMethod: After confirmation of the DHTKD1 mutations in Individual 1, Sanger sequencing confirmed compound heterozygous mutations in the same gene here.

Variant1: NM_018706.7(DHTKD1):c.1228C>T (p.Arg410Ter)

ClinVar: 39565 https://www.ncbi.nlm.nih.gov/clinvar/variation/39565/

gnomAD: 0.00005437, https://gnomad.broadinstitute.org/variant/10-12136140-C-T

Variant2: NM_018706.5(DHTKD1):c.2185G>A (p.Gly729Arg)

ClinVar: 39564 https://www.ncbi.nlm.nih.gov/clinvar/variation/39564/

gnomAD: 0.002748, https://gnomad.broadinstitute.org/variant/10-12154929-G-A

Family2to4: Maltese

FamilyPresentingHPOs: N/A

HPOsFreeText: N/A

FamilyNotHPOs: HP:0001270, HP:0007018, HP:0001252, HP:0000750, HP:0000252 (Motor delay, Attention deficit hyperactivity disorder, Muscular hypotonia, Delayed speech and language development, Microcephaly)

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Whole exome sequencing was performed as a trio with both parents. Identified DHTKD1 mutations were evaluated for possible effects and filtered for frequencies and predicted pathogenicity. No other candidate genes were found during the WES analysis for either patient sequenced. Sanger sequencing confirmed the proband's siblings are homozygous for the variant and that each parent is a carrier.

FamilyPreviousTesting: Amino acid and organic acid testing showed elevated urinary 2-aminoadipic, 2-ketoadipic, and glutaric acids in the proband as well as in two elder brothers, ages 5 and 7.

FamilyAddInfo: Parents are consanguineous, All three affected siblings are clinically normal

Variant: NM_018706.6:c.915G>C (p.Gln305His)

CAID: CA5407680 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA5407680

gnomAD: Other 0.0001630, https://gnomad.broadinstitute.org/variant/10-12131182-G-C

Affected: 3

Unaffected: 2

AddSegregationInfo: Candidate gene sequencing

Case1: Female, Mixed, Birth onset

CasePresentingHPOs: HP:0001508, HP:0000252, HP:0002076, HP:0002018, HP:0002013, HP:0011342, HP:0000750, HP:0001270, HP:0007018 (Failure to thrive, Microcephaly, Migraine, Nausea, Emesis, Mild global developmental delay, Delayed speech and language development, Motor delay, Attention deficit hyperactivity disorder)

HPOsFreeText: Seizure-like episodes, Persistent head tilting, Symptoms impreoved over time

CaseNotHPOs: HP:0001252 (Muscular hypotonia)

NotHPOsFreeText: No brain MRI abnormalities

CaseAddInfo: Parents are non-consanguineous

CasePreviousTesting: Born at full term after a pregnancy complicated by maternal hypertension with no postnatal complications; Elevated levels of plasma 2-aminoadipate (37 μmol/L, nl < 4) with elevated 2-ketoadipate (434 mmol/mol creatinine, nl < 2) and 2-hydroxyadipate (28 mmol/mol creatinine, nl < 2) in urine; Electroencephalogram, magnetic resonance imaging, and magnetic resonance angiogram of the brain were unremarkable

CaseGenotypingMethod: Whole exome sequencing was performed as a trio with both parents. Identified DHTKD1 mutations were evaluated for possible effects and filtered for frequencies and predicted pathogenicity. No other candidate genes were found during the WES analysis for either patient sequenced.

Variant1: NM_018706.6:c.2143C>T (p.Arg715Cys)

ClinVar: 242503 https://www.ncbi.nlm.nih.gov/clinvar/variation/242503/

gnomAD: 0.0002007, https://gnomad.broadinstitute.org/variant/10-12150003-C-T

Variant2: NM_018706.6(DHTKD1):c.2185G>A (p.Gly729Arg)

ClinVar: 39564 https://www.ncbi.nlm.nih.gov/clinvar/variation/39564/

gnomAD: 0.002748, https://gnomad.broadinstitute.org/variant/10-12154929-G-A