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

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

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

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