Clinical phenotype of the recurrent 1q21.1 copy-number variant

Abstract

Purpose:To characterize the clinical phenotype of the recurrent copy-number variation (CNV) at 1q21.1, we assessed the psychiatric and medical phenotypes of 1q21.1 deletion and duplication carriers ascertained through clinical genetic testing and family member cascade testing, with particular emphasis on dimensional assessment across multiple functional domains. Methods:Nineteen individuals with 1q21.1 deletion, 19 individuals with the duplication, and 23 familial controls (noncarrier siblings and parents) spanning early childhood through adulthood were evaluated for psychiatric, neurologic, and other medical diagnoses, and their cognitive, adaptive, language, motor, and neurologic domains were also assessed. Twenty-eight individuals with 1q21.1 CNVs (15 deletion, 13 duplication) underwent structural magnetic resonance brain imaging.Results: Probands with 1q21.1 CNVs presented with a range of psychiatric, neurologic, and medical disorders. Deletion and duplication carriers shared several features, including borderline cognitive functioning, impaired fine and gross motor functioning, articulation abnormalities, and hypotonia. Increased frequency of Autism Spectrum Disorder (ASD) diagnosis, increased ASD symptom severity, and increased prevalence of macrocephaly were observed in the duplication relative to deletion carriers, whereas reciprocally increased prevalence of microcephaly was observed in the deletion carriers.Conclusions: Individuals with 1q21.1 deletions or duplications exhibit consistent deficits on motor and cognitive functioning and abnormalities in head circumference.

Interstitial 1q21.1 Microdeletion Is Associated with Severe Skeletal Anomalies, Dysmorphic Face and Moderate Intellectual Disability

“…patients, however, without characterizing a distinct facial gestalt [Christiansen et al, 2004;Brunetti-Pierri et al, 2008;Mefford et al, 2008;Velinov and Dolzhanskaya, 2010;Houeijeh et al, 2011;Rosenfeld et al, 2012;Digilio et al, 2013]. Asymptomatic carriers are found in family studies with this microdeletion [Brunetti-Pierri et al, 2008;Mefford et al, 2008;Bottillo et al, 2013;Bernier et al, 2016]. According to DECIPHER (http://decipher.…”

“…The 1q21.1 deletions have been associated with a heterogeneous clinical phenotype mainly presenting with intellectual disabilities, seizures, psychosis, language disorder, autism, and microcephaly [Brunetti-Pierri et al, 2008;Stefansson et al, 2008;Basel-Vanagaite et al, 2011;Natera-De Benito et al, 2015;Bernier et al, 2016]. Congenital heart defects and a wide range of minor congenital anomalies such as frontal bossing, deep-set eyes, camptodactyly, postaxial polydactyly, mild interdigital membranes, clavicular pseudoarthrosis, rib anomalies, and syndactyly of toes 2 and 3 have been observed in these ( A , B ).…”

Recurrent Copy Number Variants Associated with Syndromic Short Stature of Unknown Cause

“…They are among the most frequently described genomic disorders. The 1p36 deletion is characterized by craniofacial dysmorphism, developmental delay, and mental retardation [33], while in 1q21.1 deletion, the presence of psychiatric or behavior alterations and cardiac abnormalities are remarkable [34, 35]. Some clinical characteristics such as developmental delay, heart defects, seizures, skeletal anomalies, and short stature were described in both syndromes [33-37].…”

A Genome Wide Copy Number Variations Analysis in Autism Spectrum Disorder (Asd) and Intellectual Disability (Id) in Italian Families

“…Casey et al identified ASD-specific risk haplotypes at 1q21.1 in three different population cluster and PDZK1 was the only gene including in the genetic region shared by all three haplotypes [29]. Furthermore, Bernier et al recently reported an increased prevalence of macrocephaly and increased ASD symptom severity in patients currying the 1q21 duplication [30].…”