Original article
Clinical and molecular characterization of 17q21.31 microdeletion syndrome in 14 French patients with mental retardation

https://doi.org/10.1016/j.ejmg.2010.11.003Get rights and content

Abstract

Chromosome 17q21.31 microdeletion was one of the first genomic disorders identified by chromosome microarrays. We report here the clinical and molecular characterization of a new series of 14 French patients with this microdeletion syndrome. The most frequent clinical features were hypotonia, developmental delay and facial dysmorphism, but scaphocephaly, prenatal ischemic infarction and perception deafness were also described. Genotyping of the parents showed that the parent from which the abnormality was inherited carried the H2 inversion polymorphism, confirming that the H2 allele is necessary, but not sufficient to generate the 17q21.31 microdeletion. Previously reported molecular analyses of patients with 17q21.31 microdeletion syndrome defined a 493 kb genomic fragment that was deleted in most patients after taking into account frequent copy number variations in normal controls, but the deleted interval was significantly smaller (205 kb) in one of our patients, encompassing only the MAPT, STH and KIAA1267 genes. As this patient presents the classical phenotype of 17q21.31 syndrome, these data make it possible to define a new minimal critical region of 160.8 kb, strengthening the evidence for involvement of the MAPT gene in this syndrome.

Introduction

Array comparative genomic hybridization (aCGH) has revolutionized the diagnosis of mental retardation through the use of a “reverse phenotyping” approach making it possible to identify recurrent genomic rearrangements before their clinical description [23]. Such techniques led to the recent characterization of novel microdeletion and microduplication syndromes [1], [23], [25]. A recurrent 17q21.31 microdeletion [Mendelian Inheritance in Man (MIM) #610443], resulting in the loss of a 500 to 650 kb region between low-copy repeat (LCR) regions, was first described in 2006 in mentally retarded individuals with a clearly recognizable clinical phenotype of mental retardation, hypotonia and characteristic facial features [12], [20], [22]. The complex genomic architecture of this microdeletion, with large clusters of LCRs at the breakpoints, suggested an underlying mechanism of non allelic homologous recombination (NAHR) [26]. A common 900 kb inversion polymorphism occurs in this region, and chromosomes with the inverted fragment in different orientations correspond to two different haplotypes, H1 and H2 [27]. The direct orientation of LCRs flanking the deleted fragment in the H2 haplotype predisposes the offspring to NAHR, favoring the generation of this microdeletion [27]. This mechanism is similar to that described for predisposing inversion polymorphisms in other microdeletion syndromes, such as Williams-Beuren syndrome (WBS), Angelman syndrome, Sotos syndrome [4], and 15q13.3 microdeletion syndrome [21]. For several chromosomal loci subject to NAHR, reciprocal deletion and duplication syndromes have been identified, including WBS and 7q11.23 duplication [24], Smith–Magenis syndrome and Potocki–Lupski syndrome [17], Prader–Willi syndrome/Angelman syndrome and 15q11q13 duplication [13], Velocardiofacial syndrome and 22q11.2 duplication [3]. However, deletions are generated at a higher rate than their reciprocal duplications [29]. The first case of duplication of the 17q21.31 region was not described until 2007 [10], in a patient with severe psychomotor developmental delay, facial dysmorphism, macrocephaly, abnormally broad fingers and toes and hirsutism. Four other patients with 17q21.31 microduplication and behavior problems and poor social interaction have also recently been reported [5].

With the use of higher resolution arrays, taking frequent copy number variations in normal controls into account, the minimal critical region involved in this 17q21.31 microdeletion syndrome was recently refined to a 424 kb region encompassing at least six genes: C17orf69, the corticotropin-releasing hormone receptor 1 gene (CRHR1) (MIM #122561), the intramembrane protease 5 gene (IMP5) (MIM #608284), the microtubule-associated protein tau gene (MAPT) (MIM #157140), the saitohin gene (STH) (MIM #607067), and KIAA1267 [11]. MAPT seems to be the most interesting of these genes for further study, because it is strongly expressed in the brain and has been implicated in several neurodegenerative diseases [18].

The largest series of patients with 17q21.31 microdeletion syndromes reported to date was studied by Koolen et al. [11], who identified a clinically recognizable phenotype, including developmental delay, childhood hypotonia and facial dysmorphism. This phenotype was recently expanded to include aortic root dilatation, recurrent joint dislocation, conductive hearing loss, dental abnormalities, the persistence of fetal fingertip pads [28], iris-choroid coloboma and partial situs inversus [19].

We present here a new series of 14 patients with the 17q21.31 microdeletion syndrome ascertained through the network of French array CGH platforms (http://www.renapa.univ-montp1.fr/) and the BACH database (https://www.genopole-lille.fr/bach/menu.php), confirming the described phenotype, refining the minimal critical region and providing further support for the role of MAPT in this syndrome. We also discuss the results of H1/H2 genotyping and parent-of-origin analysis, comparing our results with published findings.

Section snippets

Patients

A collaborative study involving the French array CGH platforms analyzing patients with mental retardation (MR), dysmorphic features and multiple congenital abnormalities (MCA) was set up for the molecular and clinical characterization of all unpublished French patients carrying the 17q21.31 microdeletion. Molecular cytogenetics analyses of 2672 MR/MCA patients showed that 14 of these patients had a 17q21.31 microdeletion. Informed consent for genetic testing was obtained from all tested

Array CGH results

All the patients studied had an overlapping heterozygous deletion of the 17q21.31 interval (Fig. 1). Oligonucleotide array CGH data identified a 493 kb region (chr17:41,073,486–41,566,599) (hg18-build36) as deleted in 11 affected individuals. In one patient (patient 7), the deletion was larger, being somewhere between 675 kb and 810 kb in size and extending to the distal part of the chromosome. However, the distal breakpoint region was a site of frequent copy number variation (CNV) in normal

Discussion

All the patients with 17q21.31 microdeletion syndrome reported here were identified by array CGH screening, by the network of French array CGH platforms, of large heterogeneous cohorts of patients with mental retardation. The calculated prevalence of 17q21.31 syndrome in our French cohort was 0.52% (14 of the 2672 patients tested), which is of the same order of magnitude as previous estimates (0.64% for Koolen et al. [11], 0.5% for Sharkey et al. [19]).

Given the copy number polymorphisms

Acknowledgments

We thank all the staff of the Biogenouest®-IBiSA (Rennes) transcriptomics platform. We also thank our colleagues for referring patients, and the patients and their families for participating in this study. This research was supported by grants from FEDER, DHOS and STIC 2004/EGMAR.

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