RESUMO
As a result of exome-based sequencing work performed by the DDD study, de novo variants in CNOT3 have emerged as a newly recognised cause of a developmental disorder. This paper describes molecular and clinical details of 16 probands with developmental disorders and de novo CNOT3 variants. It is the first such description of the developmental phenotype associated with CNOT3 variants. Eight of these cases were discovered as part of the DDD study, while the other eight were found as a result of large-scale sequencing work performed by other groups. A highly specific phenotype was not recognised in these 16 cases. The most consistent phenotypic features seen in subjects with de novo variants in CNOT3 were hypotonia, relatively small stature, developmental delay, behavioural problems and intellectual disability. There is no easily recognisable facial phenotype, but some common dysmorphic features such as anteverted nares, thin upper lip and low set eyebrows were shared among some of the probands. Haploinsufficiency appears to be the most likely mechanism of action, with eight cases found to have protein-truncating variants. Of the other eight cases (all missense variants), three share an amino acid substitution at the same position which may therefore represent an important functional domain.
Assuntos
Predisposição Genética para Doença/genética , Variação Genética , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Sequência de Aminoácidos , Comportamento , Deficiências do Desenvolvimento/genética , Exoma , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/genética , Irlanda , Aprendizagem , Masculino , Hipotonia Muscular/genética , Anormalidades Musculoesqueléticas/genética , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenótipo , Alinhamento de Sequência , Reino Unido , Sequenciamento do ExomaAssuntos
Códon sem Sentido , Coloboma/genética , Proteínas Hedgehog/genética , Deficiência Intelectual/genética , Microcefalia/genética , Fenótipo , Criança , Coloboma/diagnóstico , Fácies , Predisposição Genética para Doença , Humanos , Deficiência Intelectual/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Microcefalia/diagnóstico , Linhagem , Sequenciamento do ExomaRESUMO
Proximal 16p11.2 microdeletions are recurrent microdeletions with an overall prevalence of 0.03%. In patients with segmentation defects of the vertebra (SDV), a burden of this microdeletion was observed with TBX6 as a candidate gene for SDV. In a published cohort of patients with congenital scoliosis (CS), TBX6 haploinsufficiency was compound heterozygous with a common haplotype. Besides, a single three-generation family with spondylocostal dysostosis (SCD) was reported with a heterozygous stop-loss of TBX6. These observations questioned both on the inheritance mode and on the variable expressivity associated with TBX6-associated SDV. Based on a national recruitment of 56 patients with SDV, we describe four patients with variable SDV ranging from CS to SCD associated with biallelic variations of TBX6. Two patients with CS were carrying a proximal 16p11.2 microdeletion associated with the previously reported haplotype. One patient with extensive SDV was carrying a proximal 16p11.2 microdeletion associated with a TBX6 rare missense change. One patient with a clinical diagnosis of SCD was compound heterozygous for two TBX6 rare missense changes. The three rare variants were affecting the chromatin-binding domain. Our data illustrate the variable expressivity of recessive TBX6 ranging from CS to SCD.
