Dataset Information

HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients.

ABSTRACT: Whole-gene duplications and missense variants in the HUWE1 gene (NM_031407.6) have been reported in association with intellectual disability (ID). Increased gene dosage has been observed in males with non-syndromic mild to moderate ID with speech delay. Missense variants reported previously appear to be associated with severe ID in males and mild or no ID in obligate carrier females. Here, we report the largest cohort of patients with HUWE1 variants, consisting of 14 females and 7 males, with 15 different missense variants and one splice site variant. Clinical assessment identified common clinical features consisting of moderate to profound ID, delayed or absent speech, short stature with small hands and feet and facial dysmorphism consisting of a broad nasal tip, deep set eyes, epicanthic folds, short palpebral fissures, and a short philtrum. We describe for the first time that females can be severely affected, despite preferential inactivation of the affected X chromosome. Three females with the c.329 G > A p.Arg110Gln variant, present with a phenotype of mild ID, specific facial features, scoliosis and craniosynostosis, as reported previously in a single patient. In these females, the X inactivation pattern appeared skewed in favour of the affected transcript. In summary, HUWE1 missense variants may cause syndromic ID in both males and females.

SUBMITTER: Moortgat S

PROVIDER: S-EPMC5788272 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients.

Moortgat Stéphanie S Berland Siren S Aukrust Ingvild I Maystadt Isabelle I Baker Laura L Benoit Valerie V Caro-Llopis Alfonso A Cooper Nicola S NS Debray François-Guillaume FG Faivre Laurence L Gardeitchik Thatjana T Haukanes Bjørn I BI Houge Gunnar G Kivuva Emma E Martinez Francisco F Mehta Sarju G SG Nassogne Marie-Cécile MC Powell-Hamilton Nina N Pfundt Rolph R Rosello Monica M Prescott Trine T Vasudevan Pradeep P van Loon Barbara B Verellen-Dumoulin Christine C Verloes Alain A Lippe Charlotte von der CV Wakeling Emma E Wilkie Andrew O M AOM Wilson Louise L Yuen Amy A Study Ddd D Low Karen J KJ Newbury-Ecob Ruth A RA

European journal of human genetics : EJHG 20171127 1

Whole-gene duplications and missense variants in the HUWE1 gene (NM_031407.6) have been reported in association with intellectual disability (ID). Increased gene dosage has been observed in males with non-syndromic mild to moderate ID with speech delay. Missense variants reported previously appear to be associated with severe ID in males and mild or no ID in obligate carrier females. Here, we report the largest cohort of patients with HUWE1 variants, consisting of 14 females and 7 males, with 15 ...[more]

PMID: 29180823

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Project description:Mutations in more than 500 genes have been associated with intellectual disability (ID) and related disorders of cognitive function, such as autism and schizophrenia. Here we aimed to unravel the molecular epidemiology of non-specific ID in a genetic isolate using a combination of population and molecular genetic approaches. A large multigenerational pedigree was ascertained within a Dagestan Genetic Heritage research program in a genetic isolate of indigenous ethnics. Clinical characteristics of the affected members were based on combining diagnoses from regional psychiatric hospitals with our own clinical assessment, using a Russian translation of the structured psychiatric interviews, the Diagnostic Interview for Genetic Studies and the Family Interview for Genetic Studies, based on DSM-IV criteria. Weber/CHLC 9.0 STRs set was used for multipoint parametric linkage analyses (Simwalk2.91). Next, we checked CNVs and LOH (based on Affymetrix SNP 5.0 data) in the linked with ID genomic regions with the aim to identify candidate genes associated with mutations in linked regions. The number of statistically significant (p ? 0.05) suggestive linkage peaks with 1.3 < LOD < 3.0 we detected in a total of 10 genomic regions: 1q41, 2p25.3-p24.2, 3p13-p12.1, 4q13.3, 10p11, 11q23, 12q24.22-q24.31, 17q24.2-q25.1, 21q22.13 and 22q12.3-q13.1. Three significant linkage signals with LOD >3 were obtained at 2p25.3-p24.2 under the dominant model, with a peak at 21 cM flanked by loci D2S2976 and D2S2952; at 12q24.22-q24.31 under the recessive model, with a peak at -120 cM flanked by marker D12S2070 and D12S395 and at 22q12.3 under the dominant model, with a peak at 32 cM flanked by marker D22S683 and D22S445. After a set of genes had been designated as possible candidates in these specific chromosomal regions,we conducted an exploratory search for LOH and CNV based on microarray data to detect structural genomic variants within five ID-linked regions with LOD scores between 2.0 and 3.9. In these selected regions we obtained 173 ROH segments and 98 CN segments. Further analysis of region 2p25.3-p24.2 revealed deletions within genes encoding MYTL, SNTG2 and TPO among five of 21 affected cases at 2p25.3-p24.2. In the ID-linked region at 12q24.22-12q24.31 19 out of 21 ID cases carried segmental CNV and 20 of 21 them displayed ROH segments with mean size lengths for ID cases 2512 kb (500-6,472 kb) and for healthy control 682 kb (531-986 kb), including the genes MED13L, HRK, FBXW8, TESC, CDK2AP1 and SBNO1. Seven of 21 affected pedigree members displayed segmental deletions at 22q12.3 that includes the gene LARGE. Eight affected pedigree members carried ROH segments and 6 CN segments at 10p11.23-p11.21 containing the genes ZEB1, c10orf68 and EPC1. Our linkage and structural genomic variation analyses in a remote highland genetic isolate with aggregation of ID demonstrated that even highly isolated single kindred ID has oligo/polygenic pathogenesis. The results obtained implicate 10 genomic regions linked with ID that contain some of previously reported candidate genes, including HRK, FBXW8, TESC, CDK2AP1 and SBNO1 at 12q24 that were shown in recent studies as associated with brain measures derived from MRI scans.

Dataset Information

HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients.

Publications

HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients.

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