Chromosome 16p13.3 Duplication Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene duplication syndrome. The duplication involves chromosome 16p13.3, which is complementary to the deletion found in severe Rubinstein-Taybi syndrome (610543). The common gene duplicated is CREBBP (600140), which is mutant in classic Rubinstein-Taybi syndrome (180849).

Clinical Features

Thienpont et al. (2010) reported 12 unrelated patients with an interstitial duplication of chromosome 16p13.3. All were referred for mental retardation and/or congenital anomalies. Mental development ranged from mildly to moderately delayed with speech problems, although some had low-normal intelligence. Three patients had behavioral problems. All showed normal growth parameters, except 1 patient who had precocious puberty. Many patients shared similar facial features, including midfacial hypoplasia in young children and a longer face in older individuals. The nose was prominent with a bulbous tip, and eyes were often upslanting with narrow palpebral fissures, sometimes with ptosis. The upper lip typically was thin, and the ears low set and/or protruding. There were mild skeletal anomalies of the hands and feet, such as proximally implanted thumbs, long tapering fingers, short fifth finger, pes cavus, short toes, and camptodactyly. Less frequent findings were congenital hip dislocation in 2, vertebral fusion in 1, and congenital heart anomalies in 5. The skeletal findings suggested mild arthrogryposis.

Cytogenetics

Thienpont et al. (2010) identified 12 different interstitial duplications of chromosome 16p13.3 in 12 patients. Ten of the 12 duplications occurred de novo, and 2 were inherited from unaffected parents. The duplications ranged in size, but the smallest region of overlap was 186 to 260 kb and included the CREBBP gene. None of the breakpoints were recurrent, arguing against nonallelic homologous recombination as a mechanism. The findings indicated that CREBBP is dosage sensitive. Thienpont et al. (2010) estimated the frequency of CREBBP duplication to be 1 in 97,000 to 146,000 live births.

Sahoo et al. (2011) analyzed 38,779 individuals referred to the diagnostic laboratory for microarray testing for the presence of copy number variants encompassing 20 putative schizophrenia susceptibility loci. They also analyzed the indications for study for individuals with copy number variants overlapping those found in 6 individuals referred for schizophrenia. After excluding larger gains or losses that encompassed additional genes outside the candidate loci (e.g., whole-arm gains/losses), Sahoo et al. (2011) identified 1,113 individuals with copy number variants encompassing schizophrenia susceptibility loci and 37 individuals with copy number variants overlapping those present in the 6 individuals referred for schizophrenia. Of these, 1,035 had a copy number variant of 1 of 6 recurrent loci: 1q21.1 (612474, 612475), 15q11.2 (608636), 15q13.3 (612001), 16p11.2 (611913), 16p13.11 (see also 610543), and 22q11.2 (192430, 608363). The indications for study for these 1,150 individuals were diverse and included developmental delay, intellectual disability, autism spectrum, and multiple congenital anomalies. Sahoo et al. (2011) identified the 16p13.11 microduplication in 74 individuals; 2 were de novo, 14 maternally inherited, 16 paternally inherited, and 42 of unknown inheritance. The average age at diagnosis was 7.8 years with an age range of 0.7 to 38.6 years, with a broad range of indication for study. This microduplication was seen in 74 of 23,250 cases referred to their laboratory for a frequency of 0.32% and not at all in 5,674 controls (see Itsara et al., 2009), p less than 0.0001. The incidence in a schizophrenia population reported by Ingason et al. (2011) was 0.3% compared to 0.09% in their controls, and in the neurodevelopmental deficit population reported by Vassos et al. (2010) the frequency was 0.48% compared with the control frequency of 0.25%. Sahoo et al. (2011) concluded that the results from their study, the largest genotype-first analysis of schizophrenia susceptibility loci to that time, suggested that the phenotypic effects of copy number variants associated with schizophrenia are pleiotropic and implied the existence of shared biologic pathways among multiple neurodevelopmental conditions.