Intra-family phenotypic heterogeneity of 16p11.2 deletion carriers in a three-generation Chinese family

Abstract

The 16p11.2 deletion is a recurrent genomic event and a significant risk factor for autism spectrum disorders (ASD). This genomic disorder also exhibits extensive phenotypic variability and diverse clinical phenotypes. The full extent of phenotypic heterogeneity associated with the 16p11.2 deletion disorder and the factors that modify the clinical phenotypes are currently unknown. Multiplex families with deletion offer unique opportunities for exploring the degree of heterogeneity and implicating modifiers. Here we reported the clinical and genomic characteristics of three 16p11.2 deletion carriers in a Chinese family. The father carries a de novo 16p11.2 deletion, and it was transmitted to the proband and sib. The proband presented with ASD, intellectual disability, learning difficulty, congenital malformations such as atrial septal defect, scoliosis. His dysmorphic features included myopia and strabismus, flat and broad nasal bridge, etc. While the father shared same neurodevelopmental problems as the proband, the younger brother did not show many of the proband's phenotypes. The possible unmasked mutation of TBX6 and MVP gene in this deleted region and the differential distribution of other genomic CNVs were explored to explain the phenotypic heterogeneity in these carriers. This report demonstrated the different developmental trajectory and discordant phenotypes among family members with the same 16p11.2 deletion, thus further illustrated the phenotypic complexity and heterogeneity of the 16p11.2 deletion.

Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism

“…Other phenotypes of these rats are feeding problems (45,46), sensory neglect, and abnormal gait (30,31,(47)(48)(49). Indeed, abnormal gait and motor delay (13,16,18,50), attention deficits (13), and feeding defects (16) are common in patients with 16p11.2 deletion. Moreover, motor development problems are common in autism spectrum disorders and may serve as an indicator for early intervention, as these features appear before the core symptoms that define autism (51).…”

“…A reciprocal effect of 16p11.2 dosage on head size has been noted, as deletions are associated with large head size or macrocephaly, whereas duplications are associated with microcephaly (16). These studies reveal the variability of symptoms in patients carrying the same 16p11.2 CNV, an extreme example being a family with three affected members with symptoms so heterogeneous that they were barely overlapping (18).…”

Autism Spectrum Disorder: Developmental Approaches from Infancy through Early Childhood

“…It now seems that non-inherited de novo genetic factors, for example, copy number variants (CNVs) and point mutations, account for signifi cantly more ASD cases than had previously been thought, but each specifi c genomic variant accounts for fewer than 1 % of cases (Sebat et al, 2007 ;State & Sestan, 2012 ). Moreover, some of these recently identifi ed CNVs are associated not only with ASD but also with other neurodevelopmental disorders including, for example, schizophrenia or language impairment (Shen et al, 2011 ;Vernes et al, 2008 ).…”

Advances in Autism Research – The Genomic Basis of ASD

“…Furthermore, correlation between the phenotypes of patients harboring different-or similar-sized CNVs is confounded by extreme heterogeneity and variability of symptoms. For example, a family with three affected members harboring identical 16p11.2 deletions was recently described to have minimal symptom overlap between family members [56]. Subsequent studies have aimed at using model organisms to identify the key dosage-sensitive genes within this region that give rise to the abnormal phenotypes [29,57,58].…”