RESUMO
Utilizing trio whole-exome sequencing and a gene matching approach, we identified a cohort of 18 male individuals from 17 families with hemizygous variants in KCND1, including two de novo missense variants, three maternally inherited protein-truncating variants, and 12 maternally inherited missense variants. Affected subjects present with a neurodevelopmental disorder characterized by diverse neurological abnormalities, mostly delays in different developmental domains, but also distinct neuropsychiatric signs and epilepsy. Heterozygous carrier mothers are clinically unaffected. KCND1 encodes the α-subunit of Kv4.1 voltage-gated potassium channels. All variant-associated amino acid substitutions affect either the cytoplasmic N- or C-terminus of the channel protein except for two occurring in transmembrane segments 1 and 4. Kv4.1 channels were functionally characterized in the absence and presence of auxiliary ß subunits. Variant-specific alterations of biophysical channel properties were diverse and varied in magnitude. Genetic data analysis in combination with our functional assessment shows that Kv4.1 channel dysfunction is involved in the pathogenesis of an X-linked neurodevelopmental disorder frequently associated with a variable neuropsychiatric clinical phenotype.
Assuntos
Transtornos do Neurodesenvolvimento , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Epilepsia/genética , Sequenciamento do Exoma , Doenças Genéticas Ligadas ao Cromossomo X/genética , Heterozigoto , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/genética , Linhagem , Fenótipo , Canais de Potássio Shal/genéticaRESUMO
Loss-of-function variants in KMT2D are responsible for Kabuki syndrome type 1 (KS1). In the last 5 years, missense variants in exon 38 or 39 in KMT2D have been found in patients exhibiting a new phenotype with multiple malformations and absence of intellectual disability, distinct from KS1. To date, only 16 cases have been reported with classic features of hearing loss, abnormality of the ear, lacrimal duct defects, branchial sinus/neck pits, choanal atresia (CA), athelia, hypo(para)thyroidism, growth delay, and dental anomalies. We report here two families and one unpublished variant, refining the clinical and molecular knowledge on this new entity. Family 1 presented with apparently isolated autosomal dominant choanal atresia, in eight members across three generations. Exome sequencing (ES) in the proband and one cousin revealed a p.Glu3569Gly variant in exon 38 of KMT2D, segregating with choanal atresia in the family. Clinical reevaluation evidenced thyroid dysfunction, mild hearing anomalies, and hypoplastic nipple in some patients. Family 2 presented with nasolacrimal duct obstruction, hearing loss, mild facial features, unilateral axial polydactyly, and unilateral toe V-VI syndactyly. ES revealed a de novo already reported p.Arg3582Gln variant in exon 38 of KMT2D. Considering these results and the existing literature, we suspect that missense variants in exon 38 of KMT2D are responsible for phenotypes that are even milder (isolated CA) and broader (polydactyly) than what has been previously described.
Assuntos
Atresia das Cóanas , Perda Auditiva , Obstrução dos Ductos Lacrimais , Ducto Nasolacrimal , Polidactilia , Doenças Vestibulares , Anormalidades Múltiplas , Atresia das Cóanas/genética , Éxons , Face/anormalidades , Perda Auditiva/genética , Doenças Hematológicas , Humanos , Fenótipo , Polidactilia/genética , Doenças Vestibulares/genéticaRESUMO
Autosomal recessive primary microcephaly type 3 (MCPH3) caused by pathogenic variations in CDK5RAP2, is characterized by sensorineural hearing loss, abnormality of skin pigmentation, ocular defects and severe microcephaly associated with neurodevelopmental delay. In this study, we expand the phenotype of MCPH3 as we describe a 10-year-old girl with a biallelic exonic frameshift variant in CDK5RAP2 displaying previously unreported features usually associated with Meier-Gorlin and microcephalic osteodysplastic primordial dwarfism type II (MOPDII). We further describe the clinical phenotype of this form of centrosomal-based primary microcephaly and emphasize the importance of skeletal defect screening in affected individuals.
Assuntos
Nanismo , Microcefalia , Osteocondrodisplasias , Feminino , Humanos , Microcefalia/patologia , Nanismo/genética , Nanismo/diagnóstico , Osteocondrodisplasias/genética , Osteocondrodisplasias/diagnóstico , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/diagnóstico , Proteínas do Tecido Nervoso , Proteínas de Ciclo Celular/genéticaRESUMO
This monocentric study included fifteen children under a year old in intensive care with suspected monogenic conditions for rapid trio exome sequencing (rES) between April 2019 and April 2021. The primary outcome was the time from blood sampling to rapid exome sequencing report to parents. All results were available within 16 days and were reported to parents in or under 16 days in 13 of the 15 individuals (86%). Six individuals (40%) received a diagnosis with rES, two had a genetic condition not diagnosed by rES. Eight individuals had their care impacted by their rES results, four were discharged or died before the results. This small-scale study shows that rES can be implemented in a regional University hospital with rapid impactful diagnosis to improve care in critically ill infants.