Chromosome 16p12.2-P11.2 Deletion Syndrome, 7.1- To 8.7-Mb

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome (chr16:21.4-29.3 Mb).

Description

The chromosome 16p12.2-p11.2 deletion syndrome is characterized phenotypically by dysmorphic facial features, feeding difficulties, recurrent ear infections, developmental delay, and cognitive impairment. Additional features, such as heart defects and short stature, are variable (Ballif et al., 2007; Battaglia et al., 2009).

The pericentric region of chromosome 16, specifically involving 16p12-p11, is a structurally complex region enriched in repetitive sequence elements, rendering this region susceptible to deletion or rearrangement (Ballif et al., 2007). There are several phenotypes associated with variation in this region: see 611913 for a deletion or duplication at 16p11.2 associated with autism; see 136570 for discussion of a recurrent 520-kb deletion at 16p12.1 associated with developmental delay and craniofacial dysmorphism; and see 613444 for a 220-kb deletion at 16p11.2 associated with isolated severe early-onset obesity and obesity with developmental delay.

Battaglia et al. (2009) emphasized that the region at chromosome 16p11.2 that confers susceptibility to autism (AUTS14; see 611913) is located more centromeric to and is distinct from the 16p12.2-p11.2 region involved in the multiple congenital anomalies and intellectual disability phenotype.

Clinical Features

Hernando et al. (2002) reported the first case of multiple congenital anomalies associated with a de novo interstitial deletion of band 16p11.2 confirmed by array comparative genomic hybridization (CGH). Ultrasound examination at age 20 weeks' gestation showed cardiac defects and unilateral multiple renal cysts. At birth, the male infant showed severe intrauterine growth retardation and dysmorphic features, including flat facies, microretrognathia, blepharophimosis, short nose with hypoplastic nasal alae and absent nasal bridge, low-set and malformed ears, coloboma, and unilateral chorioretinitis. Other features included tetralogy of Fallot with pulmonary atresia, cubital deviation of the hands, talipes varus, articular limitation, and hemivertebra at level L1. He also had unilateral renal agenesis and cryptorchidism. The deletion occurred on the maternally derived chromosome. He died of cardiac failure at age 5 months. Hempel et al. (2009) noted that, contrary to subsequent patients, this infant was more severely affected and that the discrepancy may be due to a larger deletion in 16p than defined by Hernando et al. (2002).

Ballif et al. (2007) reported 4 unrelated patients with developmental disabilities and dysmorphic features associated with a recurrent de novo pericentromeric deletion in 16p11.2-p12.2. Clinical features included flat facies, downslanting palpebral fissures, low-set and malformed ears, and eye anomalies. Other commonly described features include orofacial clefting, heart defects, frequent ear infections with potential hearing loss, short stature, minor hand and foot anomalies, feeding difficulties, hypotonia, and cognitive and developmental delay. They referred to the report of Hernando et al. (2002) and concluded that the common clinical features constituted a previously undescribed syndrome.

Battaglia et al. (2009) reported an 8-year-old girl with developmental delay, poor speech, and mild dysmorphic features, including flat, hypotonic face, low-set, posteriorly rotated ears, high-arched palate, thin upper lip, and long, thin fingers. There were frequent ear infections and feeding difficulties. She was hyperactive with short attention span and difficulty in concentration, but did not have autism. Battaglia et al. (2009) noted the phenotypic similarities to the individuals described by Ballif et al. (2007).

Hempel et al. (2009) reported a 13-year-old boy with delayed development, moderate mental retardation, and significant delay in speech development associated with a 16p12-p11.2 deletion. He had minor facial anomalies, such as a long, flat face, a high and broad forehead, frontal upsweep of the hair, deep-set eyes, long nose with bulbous nasal tip, short, smooth philtrum, and small mouth. He had feeding problems beginning in infancy and continuing, as well as recurrent ear infections with mild mixed hearing loss. He also had hypotonia, delayed motor development, and lasting deficits in fine motor skills. Autism could be excluded.

Cytogenetics

By microarray-based comparative genomic hybridization of samples from 8,789 patients referred for developmental disabilities, Ballif et al. (2007) identified a recurrent de novo pericentric deletion in 16p12.2-p11.2 in 4 unrelated patients. All 4 deletions shared the same distal breakpoint, located approximately 21.4 Mb from the 16p telomere. However, the proximal breakpoints were variable, at 28.5 Mb, 29.3 Mb (in 2 patients), and 30.1 Mb from the 16p telomere, resulting in overall deletion sizes of 7.1 Mb, 7.9 Mb, and 8.7 Mb, respectively. The smallest region of overlap was about 7.1 Mb. The identification of complex segmental duplications flanking the deletion regions suggested that nonallelic homologous recombination (NAHR) mediated these rearrangements.

In a girl with developmental delay and mild dysmorphic features, Battaglia et al. (2009) identified a heterozygous de novo 8.2-Mb deletion at 16p12.2-p11.2. The distal breakpoint was the same as the distal breakpoint found in the patients reported by Ballif et al. (2007).

Hempel et al. (2009) found a de novo 7.7-Mb deletion on 16p12.2-p11.2 in a boy with mental retardation and mild dysmorphic features. Both breakpoints were flanked by numerous segmental duplications. The distal breakpoint was 21.5 Mb from the 16p telomere, which was considered likely to be the same as that reported by Ballif et al. (2007).