RESUMO
The recurrent chromosome 16p11.2 BP4-BP5 microdeletion (MIM #611913) predisposes to a neurodevelopmental disorder with variable associated congenital anomalies and susceptibility to early-onset obesity. We identified 22 new individuals with proximal 16p11.2 deletions through retrospective data analysis at our institution and performed phenotyping through in-depth chart review. Our cohort exhibited a spectrum of neurodevelopmental abnormalities largely consistent with other publications, however they also were found to have a higher rate than expected of congenital anomalies, some of which have not yet been reported in association with 16p11.2 microdeletions to our knowledge. This series contributes to the body of data on this population, which we anticipate will continue to evolve along with increased uptake of genetic testing.
RESUMO
Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K+ channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann-Laband and Temple-Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K+ conductance, referred to as syndromic neurodevelopmental K+ channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.
Assuntos
Anormalidades Múltiplas/genética , Canalopatias/genética , Anormalidades Craniofaciais/genética , Canais de Potássio Éter-A-Go-Go/genética , Fibromatose Gengival/genética , Mutação com Ganho de Função , Hallux/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Unhas Malformadas/genética , Canais de Potássio/genética , Canais de Potássio Ativados por Cálcio de Condutância Baixa/genética , Polegar/anormalidades , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Canalopatias/patologia , Criança , Anormalidades Craniofaciais/patologia , Feminino , Fibromatose Gengival/patologia , Hallux/patologia , Deformidades Congênitas da Mão/patologia , Humanos , Deficiência Intelectual/patologia , Masculino , Unhas Malformadas/patologia , Fenótipo , Polegar/patologiaRESUMO
We describe six individuals with microdeletions and microduplications in the distal 22q11.2 region detected by microarray. Five of the abnormalities have breakpoints in the low-copy repeats (LCR) in this region and one patient has an atypical rearrangement. Two of the six patients with abnormalities in the region between LCR22 D-E have hearing loss, which has previously been reported only once in association with these abnormalities. We especially note the behavioral/neuropsychiatric problems, including the severity and early onset, in patients with distal 22q11.2 rearrangements. Our patients add to the genotype-phenotype correlations which are still being generated for these chromosomal anomalies.