RESUMO
Many genetic testing methodologies are biased towards picking up structural variants (SVs) that alter copy number. Copy-neutral rearrangements such as inversions are therefore likely to suffer from underascertainment. In this study, manual review prompted by a virtual multidisciplinary team meeting and subsequent bioinformatic prioritisation of data from the 100K Genomes Project was performed across 43 genes linked to well-characterised skeletal disorders. Ten individuals from three independent families were found to harbour diagnostic inversions. In two families, inverted segments of 1.2/14.8 Mb unequivocally disrupted GLI3 and segregated with skeletal features consistent with Greig cephalopolysyndactyly syndrome. For one family, phenotypic blending was due to the opposing breakpoint lying ~45 kb from HOXA13 In the third family, long suspected to have Marfan syndrome, a 2.0 Mb inversion disrupting FBN1 was identified. These findings resolved lengthy diagnostic odysseys of 9-20 years and highlight the importance of direct interaction between clinicians and data-analysts. These exemplars of a rare mutational class inform future SV prioritisation strategies within the NHS Genomic Medicine Service and similar genome sequencing initiatives. In over 30 years since these two disease-gene associations were identified, large inversions have yet to be described and so our results extend the mutational spectra linked to these conditions.
Assuntos
Doenças do Desenvolvimento Ósseo , Inversão Cromossômica , Humanos , Sequência de Bases , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Inversão Cromossômica/genética , Mapeamento Cromossômico , Fibrilina-1/genética , Testes Genéticos , Mutação , Proteínas do Tecido Nervoso/genética , Proteína Gli3 com Dedos de Zinco/genéticaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
PURPOSE: Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported. METHODS: We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review. RESULTS: We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype- phenotype correlations show that late-truncating pathogenic variants (exons 16-17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction. CONCLUSION: Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.
Assuntos
Deficiências do Desenvolvimento/genética , Histona Acetiltransferases/genética , Deficiência Intelectual/genética , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Deficiências do Desenvolvimento/fisiopatologia , Exoma/genética , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Deficiência Intelectual/fisiopatologia , Masculino , Microcefalia/genética , Microcefalia/fisiopatologia , Mutação , Fenótipo , Isoformas de Proteínas/genética , Adulto JovemAssuntos
Testes Genéticos , Neoplasias , Humanos , Consenso , Predisposição Genética para Doença , Células Germinativas , Reino UnidoRESUMO
Pontocerebellar hypoplasia type 10 (PCH10) is a progressive autosomal recessive neurodegenerative disorder that has been recently described in association with cleavage and polyadenylation factor I subunit 1 (CLP1) mutations. To date, all reported cases have the same homozygous missense mutation in the CLP1 gene suggesting a founder mutation. CLP1 is an RNA kinase involved in tRNA splicing and maturation. There is evidence that the mutation is associated with functionally impaired kinase activity and subsequent defective tRNA processing. Through whole exome sequencing, we identified the same mutation in an extended family of Turkish origin. Both children presented with severe psychomotor delay, progressive microcephaly, and constipation. However, intrafamilial phenotypic variability is suggested due to the variability in their brain abnormalities and clinical features.