RESUMO
Glutaric aciduria type 1 (GA1, deficiency of glutaryl CoA dehydrogenase, glutaric acidemia type 1) (ICD-10 code: E72.3; MIM 231670) is an autosomal recessive disease caused by mutations in the gene encoding the enzyme glutaryl CoA dehydrogenase (GCDH). Herein, we present the biochemical and molecular genetic characteristics of 51 patients diagnosed with GA1 from 49 unrelated families in Russia. We identified a total of 21 variants, 9 of which were novel: c.127 + 1G > T, Ñ.471_473delCGA, c.161 T > C (p.Leu54Pro), c.531C > A (Ñ.Phe177Leu), c.647C > T (p.Ser216Leu), c.705G > A (Ñ.Gly235Asp), c.898 G > A (Ñ.Gly300Ser), c.1205G > C (Ñ.Arg402Pro), c.1178G > A (Ñ.Gly393Glu). The most commonly detected missense variants were c.1204C > T (p.Arg402Trp) and Ñ.1262C > T (Ñ.Ala421Val), which were identified in 56.38% and 11.7% of mutated alleles. A heterozygous microdeletion of the short arm (p) of chromosome 19 from position 12,994,984-13,003,217 (8233 b.p.) and from position 12,991,506-13,003,217 (11,711 b.p.) were detected in two patients. Genes located in the area of imbalance were KLF1, DNASE2, and GCDH. Patients presented typical GA1 biochemical changes in the biological fluids, except one patient with the homozygous mutation p.Val400Met. No correlation was found between the GCDH genotype and glutaric acid (GA) concentration in the cohort of our patients.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/epidemiologia , Erros Inatos do Metabolismo dos Aminoácidos/genética , Encefalopatias Metabólicas/epidemiologia , Encefalopatias Metabólicas/genética , Glutaril-CoA Desidrogenase/química , Glutaril-CoA Desidrogenase/deficiência , Glutaril-CoA Desidrogenase/genética , Mutação de Sentido Incorreto/genética , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Encefalopatias Metabólicas/diagnóstico , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estrutura Secundária de Proteína , Federação Russa/epidemiologiaRESUMO
Intellectual disability is the most common developmental disorder caused by chromosomal aberrations as well as single-nucleotide variants (SNVs) and small insertions/deletions (indels). Here we report identification of a novel, probably pathogenic mutation in the WHSC1 gene in a patient case with phenotype overlapping the features of Wolf-Hirschhorn syndrome. Deletions involving WHSC1 (Wolf-Hirschhorn syndrome candidate 1 gene) were described earlier in patients with Wolf-Hirschhorn syndrome. However, to our knowledge, single-point mutations in WHSC1 associated with any intellectual deficiency syndromes have not been reported. Using whole exome sequencing, we found a de novo nonsense mutation in WHSC1 (c.3412C>T, p.Arg1138Ter, NM_001042424.2) in patient with syndromic intellectual disability. This finding is challenging regarding a possible causative role of WHSC1 in intellectual disability syndromes, specifically Wolf-Hirschhorn syndrome. From the clinical standpoint, our finding suggests that next-generation sequencing along with chromosome microarray analysis (CMA) might be useful in genetic testing for patients with intellectual disability and dysmorphic features.
Assuntos
Códon sem Sentido/genética , Predisposição Genética para Doença , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Proteínas Repressoras/genética , Síndrome de Wolf-Hirschhorn/genética , Sequência de Aminoácidos , Sequência de Bases , Feminino , Histona-Lisina N-Metiltransferase/química , Humanos , Lactente , Masculino , Linhagem , Proteínas Repressoras/químicaRESUMO
BACKGROUND: Because of the significant occurrence of "WAGR-region" deletions among de novo mutations detected in congenital aniridia, DNA diagnosis is critical for all sporadic cases of aniridia due to its help in making an early diagnosis of WAGR syndrome. Standard cytogenetic karyotype study is a necessary step of molecular diagnostics in patients with deletions and in the patients' parents as it reveals complex chromosomal rearrangements and the risk of having another affected child, as well as to provide prenatal and/or preimplantation diagnostics. CASE PRESENTATION: DNA samples were obtained from the proband (a 2-year-old boy) and his two healthy parents. Molecular analysis revealed a 977.065 kb deletion that removed loci of the ELP4, PAX6, and RCN1 genes but did not affect the coding sequence of the WT1 gene. The deletion occurred de novo on the paternal allele. The patient had normal karyotype 46,XY and a de novo pericentric inversion of chromosome 11, inv(11)(p13q14). CONCLUSIONS: We confirmed the diagnosis of congenital aniridia at the molecular level. For the patient, the risk of developing Wilms' tumor is similar to that in the general population. The recurrence risk for sibs in the family is low, but considering the possibility of gonadal mosaicism, it is higher than in the general population.