Original article
Extending the phenotype of recurrent rearrangements of 16p11.2: Deletions in mentally retarded patients without autism and in normal individuals

https://doi.org/10.1016/j.ejmg.2009.03.006Get rights and content

Abstract

Array CGH (comparative genomic hybridization) screening of large patient cohorts with mental retardation and/or multiple congenital anomalies (MR/MCA) has led to the identification of a number of new microdeletion and microduplication syndromes. Recently, a recurrent copy number variant (CNV) at chromosome 16p11.2 was reported to occur in up to 1% of autistic patients in three large autism studies.

In the screening of 4284 patients with MR/MCA with various array platforms, we detected 22 individuals (14 index patients and 8 family members) with deletions in 16p11.2, which are genomically identical to those identified in the autism studies. Though some patients shared a facial resemblance and a tendency to overweight, there was no evidence for a recognizable phenotype. Autism was not the presenting feature in our series.

The assembled evidence indicates that recurrent 16p11.2 deletions are associated with variable clinical outcome, most likely arising from haploinsufficiency of one or more genes. The phenotypical spectrum ranges from MR and/or MCA, autism, learning and speech problems, to a normal phenotype.

Introduction

Array CGH (comparative genomic hybridization) screening of large patient cohorts with mental retardation (MR) and/or multiple congenital anomalies (MCA) has lead to the identification of a number of new microdeletion and microduplication syndromes (for recent review, see [20]). An additional and important outcome of this testing has been the discovery that several recurrent microdeletion and microduplication syndromes are caused by non-allelic homologous recombination (NAHR) between paired segmental duplications. As the short arm of chromosome 16 is rich in intrachromosomal segmental duplications (also known as low copy repeats, LCRs), it has previously been suggested that this region may harbour novel genomic disorders [19]. Indeed, a number of recent reports have provided evidence for this. Ballif et al. identified a microdeletion syndrome in 16p11.2–p12.2 involving a 7–8 Mb deletion [1]. Ullman et al. reported reciprocal 16p13.1 deletions and duplications which predispose to MR and/or autism [21], while Hannes et al. found that this deletion was significantly associated with MR/MCA, and that the reciprocal duplication was a common variant in the general population [8]. Finally, copy number variants (CNVs) in the region of 16p11.2 have been identified in up to 1% of autistic individuals [10], [13], [22], representing a substantial susceptibility risk to development of autism. The phenotypic spectrum of rearrangements in this genomic region remains to be fully characterized, especially in regard to their association with autism.

By screening 4284 patients with MR/MCA, we detected 14 patients with deletions in 16p11.2, which are genomically identical to those identified in the autism studies [10], [13], [22]. Of these, six deletions were de novo and six were inherited from parents with a milder or normal phenotype; in one index case the inheritance could not be assessed, in another case segregation analysis is pending. We also detected an inherited smaller deletion of an adjacent region on 16p11.2.

Here we present clinical and molecular data on our patients with a 16p11.2 deletion and compare them with previously reported cases. As autism was not the presenting symptom in our series of patients, our data indicate that the recurrent deletion of 16p11.2 gives rise to a broader phenotype than autism alone.

Section snippets

Selection of patients tested by various array platforms

We studied 4284 patients with MR/MCA in several genetic centres. Patients were ascertained by clinical geneticists in Leiden, The Netherlands (n = 318), and through a collaborative effort with cytogenetic laboratories of Groningen, The Netherlands (n = 600), Nijmegen, The Netherlands (n = 1525), Stockholm, Sweden (n = 560), Melbourne, Australia (n = 325), Madrid, Spain (n = 60), and Ghent, Belgium (n = 896).

Array platforms

Each of the genetic centres used one of the following array platforms to analyse their group of

Recurrent microdeletion of 16p11.2

Array analysis was performed on 4284 patients with MR/MCA. We detected 14 cases (0.3%) with a microdeletion of approximately 600 kb in the same area of 16p11.2, from genomic location 29.5 to 30.1 Mb (Ensembl release 52, December 2008) (Fig. 3). In case 14 a de novo deletion of 16p11.2 was found in a mosaic state (Fig. 4). Table 1 summarizes all detected 16p11.2 deletions in the index cases (n = 14). Of these, six occurred de novo, six were inherited (three paternal and three maternal), one could

Discussion

We describe 22 individuals (14 index patients and 8 family members) carrying a common deletion in 16p11.2 (from genomic location 29.5 Mb to 30.1 Mb), one of them in mosaic form. In addition, two related patients showed a smaller deletion of an adjoining region, presumably representing a rearrangement of adjacent LCRs.

Previous reports have shown that the same (∼600 kb) 16p11.2 deletion recurrently occurs in patients diagnosed with autism [10], [13], [22]. Weiss et al. reported a recurrent

Acknowledgments

We would like to thank the patients and their families for their kind collaboration, and Jacqueline Schoumans, Clinical Genetics Stockholm, for bringing case 9 to our attention.

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