Clinical research
15q11.2 microdeletion (BP1–BP2) and developmental delay, behaviour issues, epilepsy and congenital heart disease: A series of 52 patients

https://doi.org/10.1016/j.ejmg.2015.01.002Get rights and content

Abstract

Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Our goal was to investigate the phenotypes associated with this microdeletion in a cohort of 52 patients.

This copy number variation (CNV) was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. This was studied by array-CGH at six different French Genetic laboratories. We collected data from 52 unrelated patients (including 3 foetuses) after excluding patients with an associated genetic alteration (known CNV, aneuploidy or known monogenic disease).

Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, ‘de novo’ microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients.

Our results support the hypothesis that 15q11.2 (BP1–BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. The later feature has been rarely described. Incomplete penetrance and variability of expression demands further assessment and studies.

Introduction

Array-CGH in human genetics has led to the detection of new submicroscopic genomic disorders, associated with an increased risk of developmental delay, psychological issues and/or epilepsy. Some CNVs are well known and classified as pathogenic or polymorphic. But, the CNVs for which an association to phenotype is unclear are known as Variant Of Unknown Significance (VOUS). The proximal long arm of chromosome 15 is a region rich in segmental duplications, that house five breakpoints (BP) for recurrent 15q CNVs as defined by non-allelic homologous recombination. The microdeletion, extending from BP1 to BP3 (type 1) or from imprinted region BP2 to BP3 (type 2), cause Prader–Willi/Angelman syndrome, depending on the parental origin of the deleted allele (Fig. 1) [Christian et al., 1999]. 15q13.3 microdeletion, between BP4 and BP5; comprising CHRNA7 gene causes mild to moderate intellectual disabilities associated to epilepsy with a variable phenotype [Masurel-Paulet et al., 2010, Shinawi et al., 2009].

Previous publications have reported patients with 15q11.2 microdeletion between BP1 and BP2 presenting with developmental delay, speech impairment, learning disabilities and/or behavioural issues [Abdelmoity et al., 2012, Burnside et al., 2011, Doornbos et al., 2009, Madrigal et al., 2012, Murthy et al., 2007, Sempere Pérez et al., 2011, von der Lippe et al., 2011]. Nevertheless, several patients harboured another associated genetic alteration and added confusion to genotype–phenotype correlations. In addition, this CNV is frequently inherited from unaffected parent; thus the pathogenicity of 15q11.2 microdeletion seem unclear, leading to its interpretation as VOUS.

The goal of the present study therefore was to refine the phenotype associated with this 15q11.2 microdeletion by description of a large and multicentre series of patients without a known associated pathogenic genetic alteration.

Section snippets

Patients

A total of 9852 patients were referred for array-CGH during January 2008 to February 2013 because of intellectual deficiency, behaviour issues and/or multiple congenital abnormalities, in several genetics departments in France (Lille, Poitiers, Montpellier, Poissy, Rouen and Paris). Informed consent was obtained from all the patients and/or their parents. A 15q11.2 microdeletion was identified in 80 patients out of referrals. Twenty eight patients were excluded from the study because of an

Results

The prevalence of 15q11.2 microdeletion (BP1–BP2) was 0.8% (80/9852) in the population under study by array-CGH. Unclearly defined segmental duplications and a centromeric polymorphic region (BP1 and BP2) extend respectively between chr15:20408283–22784523 and chr15:23047696–23487533 due to different microarray platforms.

We collected clinical data of 52 unrelated patients. The sex ratio was 1.5 (31 males versus 21 females). In three prenatal cases, array-CGH was performed because no non-genetic

Discussion

An interest in BP1–BP2 region was generated due to observation of significant phenotypic differences in patients harbouring BP1–BP3 (type 1) deletion and BP2–BP3 (type 2) deletion in Prader–Willi and Angelman syndromes. In Prader–Willi syndrome, some authors observed a severe phenotype in patients with type 1 deletion than type 2 deletion considering the behavioural pattern, reading impairment, mathematical skills and visual-motor integration [Bittel et al., 2006, Butler et al., 2004, Hartley

Conclusion

We confirmed the association of 15q11.2 (BP1–BP2) microdeletion with mild/moderate intellectual deficiency, behavioural issues, speech impairment and epilepsy, and with non-specific congenital heart disease; the later has been described rarely. The core phenotype of this deletion seems to be mild intellectual deficiency with speech impairment, attention deficit and hyperactivity disorder.

Cardiac or cerebral malformations are described less frequently. An ascertainment bias has to be considered

Conflict of interest

We declare no conflict of interest.

Acknowledgements

We thank the patients and their parents for their participation to this study.

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      The familial transmission of 15q11.2 (BP1-BP2) microdeletion encompassing TUBGCP5, CYFIP1, NIPA2 and NIPA1 has been reported to be associated with phenotypic abnormalities [19,20]. Chromosome 15q11.2 (BP1-BP2) deletion syndrome [Online Mendelian Inheritance in Man (OMIM) 615656] is an autosomal dominant disorder with incomplete penetrance and phenotypic variability, and is mainly characterized by neuropsychiatric or neurodevelopmental disorders such as psychomotor developmental delay, obsessive-compulsive disorder, speech delay, autism spectrum disorder, attention deficit hyperactivity disorder and seizures [21–24], and other possible disorders of cataracts, tracheo-esophageal fistula, congenital arthrogryposis, hypoplastic left heart syndrome and congenital heart defects [25–29]. The critical deleted region in chromosome 15q11.2 deletion syndrome includes four non-imprinted genes of NIPA1 (OMIM 608145), NIPA2 (OMIM 608146), CYFIP1 (OMIM 606322) and TUBGCP5 (OMIM 608147) of which all play important roles in brain development and function.

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