Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother

Abstract

The pericentromeric region of chromosome 16p is rich in segmental duplications that predispose to rearrangements through non-allelic homologous recombination. Several recurrent copy number variations have been described recently in chromosome 16p. 16p11.2 rearrangements (29.5-30.1 Mb) are associated with autism, intellectual disability (ID) and other neurodevelopmental disorders. Another recognizable but less common microdeletion syndrome in 16p11.2p12.2 (21.4 to 28.5-30.1 Mb) has been described in six individuals with ID, whereas apparently reciprocal duplications, studied by standard cytogenetic and fluorescence in situ hybridization techniques, have been reported in three patients with autism spectrum disorders. Here, we report a multiplex family with three boys affected with autism, including two monozygotic twins carrying a de novo 16p11.2p12.2 duplication of 8.95 Mb) characterized by single-nucleotide polymorphism array, encompassing both the 16p11.2 and 16p11.2p12.2 regions. The twins exhibited autism, severe ID, and dysmorphic features, including a triangular face, deep-set eyes, large and prominent nasal bridge, and tall, slender build. The eldest brother presented with autism, mild ID, early-onset obesity and normal craniofacial features, and carried a smaller, overlapping 16p11.2 microdeletion of 847 kb (28.40-29.25 Mb), inherited from his apparently healthy father. Recurrent deletions in this region encompassing the SH2B1 gene were recently reported in early-onset obesity and in individuals with neurodevelopmental disorders associated with phenotypic variability. We discuss the clinical and genetic implications of two different 16p chromosomal rearrangements in this family, and suggest that the 16p11.2 deletion in the father predisposed to the formation of the duplication in his twin children.

SH2B1 regulation of energy balance, body weight, and glucose metabolism

“…SH2B1 rs8055982 is associated with severe obesity in children of European ancestry [97] . Aside from SH2B1 SNPs, chromosomal 16p11.2 deletion is associated with severe obesity in European cohorts [112][113][114][115] . The deleted region contains the SH2B1 gene.…”

“…Thus, SH2B1 also regulates nutrient metabolism by a body weight-independent mechanism. SH2B1 may regulate multiple physiological processes in humans: Chromosomal 16p11.2 deletion, which results in loss of SH2B1, is associated with cognitive deficits, developmental delays [112][113][114][115] , and autism [115] . Chromosomal 16p11.2 deletion is also linked to abnormal renal and enteric development in humans [124] .…”

Triplication of 16p12.1p12.3 associated with developmental and growth delay and distinctive facial features

“…All five genes have been described in conditions that demonstrate disease resulting from haploinsufficiency or loss of function of the gene product, so it is unclear whether triplication of these genes contribute to our patients' phenotypes. Evidence for dosage-sensitive genes in the 16p11.2-12.2 region is supported by previous reports of duplications associated with phenotypes including developmental delay, dysmorphic features, intellectual disability, autism spectrum disorder, microcephaly, short stature, and tapered fingers [Finelli et al, 2004;Behjati et al, 2008;Bourthoumieu et al, 2008;Tabet et al, 2012;Barber et al, 2013].…”

“…Of these, the most common is the 550 kb microdeletion at 16p11.2 that is estimated to be present in 1% of patients with autism spectrum disorder (ASD) [Weiss et al, 2008]. Duplications involving 16p11.1p13.1 [Kirchhoff et al, 2005], 16p11.2p12.1 [Engelen et al, 2002;Bourthoumieu et al, 2008], 16p11.2p12.2 [Finelli et al, 2004;Pani et al, 2010;Tabet et al, 2012;Barber et al, 2013], 16p11.2p13.1 [Behjati et al, 2008], 16p12.1p12.2 [Ballif et al, 2007], and 16p12.2 [Marshall et al, 2008;Itsara et al, 2009] have also been reported in association with neurodevelopmental disorders, congenital anomalies, and dysmorphic features, suggesting that a number of dosage-sensitive genes reside in that region. There is a single report of triplication involving 16p12.1 in a patient with intellectual disability, dysmorphic facial features, short stature, and hypotonia [Ballif et al, 2007].…”

A clinical study of patients with pericentromeric deletion and duplication within 16p12.2–p11.2

“…Reciprocal duplications of 16p12.2-p11.2 have been reported in some patients with mild to severe intellectual disability, ASD, and dysmorphic features [Engelen et al, 2002;Finelli et al, 2004;Ballif et al, 2007;Tabet et al, 2012;Barber et al, 2013]. The 16p12.2-p11.2 duplication syndrome shows variable phenotype.…”