RESUMEN
The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B-related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B-related disorders.
Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Histona Acetiltransferasas/genética , Mutación , Fenotipo , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Alelos , Blefarofimosis/diagnóstico , Blefarofimosis/genética , Estudios de Cohortes , Hipotiroidismo Congénito/diagnóstico , Hipotiroidismo Congénito/genética , Anomalías Craneofaciales/diagnóstico , Anomalías Craneofaciales/genética , Facies , Asesoramiento Genético , Sitios Genéticos , Genotipo , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/genética , Riñón/anomalías , Masculino , Rótula/anomalías , Trastornos Psicomotores/diagnóstico , Trastornos Psicomotores/genética , Escroto/anomalías , Anomalías Urogenitales/diagnóstico , Anomalías Urogenitales/genéticaRESUMEN
PURPOSE: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. METHODS: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. RESULTS: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. CONCLUSION: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.
Asunto(s)
Discapacidad Intelectual , Trastornos del Neurodesarrollo , Niño , Discapacidades del Desarrollo/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/genética , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Convulsiones/genética , Secuenciación del ExomaRESUMEN
Enzyme-based newborn screening for Mucopolysaccharidosis type I (MPS I) has a high false-positive rate due to the prevalence of pseudodeficiency alleles, often resulting in unnecessary and costly follow up. The glycosaminoglycans (GAGs), dermatan sulfate (DS) and heparan sulfate (HS) are both substrates for α-l-iduronidase (IDUA). These GAGs are elevated in patients with MPS I and have been shown to be promising biomarkers for both primary and second-tier testing. Since February 2016, we have measured DS and HS in 1213 specimens submitted on infants at risk for MPS I based on newborn screening. Molecular correlation was available for 157 of the tested cases. Samples from infants with MPS I confirmed by IDUA molecular analysis all had significantly elevated levels of DS and HS compared to those with confirmed pseudodeficiency and/or heterozygosity. Analysis of our testing population and correlation with molecular results identified few discrepant outcomes and uncovered no evidence of false-negative cases. We have demonstrated that blood spot GAGs analysis accurately discriminates between patients with confirmed MPS I and false-positive cases due to pseudodeficiency or heterozygosity and increases the specificity of newborn screening for MPS I.
