RESUMEN
We report 24 unrelated individuals with deletions and 17 additional cases with duplications at 10q11.21q21.1 identified by chromosomal microarray analysis. The rearrangements range in size from 0.3 to 12 Mb. Nineteen of the deletions and eight duplications are flanked by large, directly oriented segmental duplications of >98% sequence identity, suggesting that nonallelic homologous recombination (NAHR) caused these genomic rearrangements. Nine individuals with deletions and five with duplications have additional copy number changes. Detailed clinical evaluation of 20 patients with deletions revealed variable clinical features, with developmental delay (DD) and/or intellectual disability (ID) as the only features common to a majority of individuals. We suggest that some of the other features present in more than one patient with deletion, including hypotonia, sleep apnea, chronic constipation, gastroesophageal and vesicoureteral refluxes, epilepsy, ataxia, dysphagia, nystagmus, and ptosis may result from deletion of the CHAT gene, encoding choline acetyltransferase, and the SLC18A3 gene, mapping in the first intron of CHAT and encoding vesicular acetylcholine transporter. The phenotypic diversity and presence of the deletion in apparently normal carrier parents suggest that subjects carrying 10q11.21q11.23 deletions may exhibit variable phenotypic expressivity and incomplete penetrance influenced by additional genetic and nongenetic modifiers.
Asunto(s)
Anomalías Múltiples/genética , Aberraciones Cromosómicas , Factores de Crecimiento Nervioso/genética , Duplicaciones Segmentarias en el Genoma/genética , Eliminación de Secuencia , Proteínas de Transporte Vesicular de Acetilcolina/genética , Niño , Preescolar , Mapeo Cromosómico , Cromosomas Humanos Par 10 , Variaciones en el Número de Copia de ADN , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/genética , Femenino , Variación Genética , Recombinación Homóloga , Humanos , Hibridación Fluorescente in Situ , Lactante , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , PenetranciaRESUMEN
BACKGROUND: The introduction of molecular karyotyping technologies facilitated the identification of specific genetic disorders associated with imbalances of certain genomic regions. A detailed phenotypic delineation of interstitial 16p13.3 duplications is hampered by the scarcity of such patients. OBJECTIVES: To delineate the phenotypic spectrum associated with interstitial 16p13.3 duplications, and perform a genotype-phenotype analysis. RESULTS: The present report describes the genotypic and phenotypic delineation of nine submicroscopic interstitial 16p13.3 duplications. The critically duplicated region encompasses a single gene, CREBBP, which is mutated or deleted in Rubinstein-Taybi syndrome. In 10 out of the 12 hitherto described probands, the duplication arose de novo. CONCLUSIONS: Interstitial 16p13.3 duplications have a recognizable phenotype, characterized by normal to moderately retarded mental development, normal growth, mild arthrogryposis, frequently small and proximally implanted thumbs and characteristic facial features. Occasionally, developmental defects of the heart, genitalia, palate or the eyes are observed. The frequent de novo occurrence of 16p13.3 duplications demonstrates the reduced reproductive fitness associated with this genotype. Inheritance of the duplication from a clinically normal parent in two cases indicates that the associated phenotype is incompletely penetrant.