Original article
Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome

https://doi.org/10.1016/j.ejmg.2009.02.006Get rights and content

Abstract

Interstitial deletions of 7q11.23 cause Williams–Beuren syndrome, one of the best characterized microdeletion syndromes. The clinical phenotype associated with the reciprocal duplication however is not well defined, though speech delay is often mentioned. We present 14 new 7q11.23 patients with the reciprocal duplication of the Williams–Beuren syndrome critical region, nine familial and five de novo. These were identified by either array-based MLPA or by array-CGH/oligonucleotide analysis in a series of patients with idiopathic mental retardation with an estimated population frequency of 1:13,000–1:20,000. Variable speech delay is a constant finding in our patient group, confirming previous reports. Cognitive abilities range from normal to moderate mental retardation. The association with autism is present in five patients and in one father who also carries the duplication. There is an increased incidence of hypotonia and congenital anomalies: heart defects (PDA), diaphragmatic hernia, cryptorchidism and non-specific brain abnormalities on MRI.

Specific dysmorphic features were noted in our patients, including a short philtrum, thin lips and straight eyebrows. Our patient collection demonstrates that the 7q11.23 microduplication not only causes language delay, but is also associated with congenital anomalies and a recognizable face.

Introduction

The Williams–Beuren syndrome (WBS) is a well-characterized microdeletion syndrome, caused by deletion of a 1.4–1.5 Mb region located at 7q11.23 [4], [13], [16]. WBS patients have a very distinctive phenotype including a typical facial dysmorphism, frequent cardiac defects, short stature, infantile hypercalcemia and a specific cognitive profile. Different genes have been linked to specific clinical manifestations of this contiguous gene syndrome. The elastin gene (ELN) lies at the centre of the common deleted interval and has unequivocally been associated with the supra-valvular aortic stenosis in WBS. Other genes involved are BAZ1B, which has been linked to the hypercalcemia and LIMK1, CYLN2, GTF2I, all linked to aspects of cognitive delay. The GTF2IRD1 gene is thought to be responsible for the craniofacial pathology [10].

The microdeletion arises by nonallelic homologous recombination (NAHR) between low copy repeats flanking the deleted region. Because of this genomic architecture, the reciprocal duplication of this region can be anticipated to exist, but only 14 cases have been reported so far. Somerville et al. was the first to describe a patient with a de novo duplication of the WBS region in 2005 [14]. This male patient displayed severe expressive language delay, hypotonia in infancy, mild developmental delay and mild dysmorphic features as a high broad nose, thin lips, a short philtrum and facial asymmetry. Kriek et al. detected two patients when screening a cohort of 105 patients with mental retardation and multiple congenital abnormalities (MR/MCA) [8]. Only one of these had a delay in language development, the other patient had a normal mental development, a severe heart malformation and craniosynostosis but only carried a duplication of a very small part of the WBS region (0.3–0.4 Mb), encompassing the FKBP6 gene which is expressed in male germ cells and therefore unlikely to cause the clinical manifestations observed in this patient. Since these initial case reports, 11 more patients have been reported [1], [3], [7], [18], [20]. All were detected in cohorts of patients with either mental retardation, epilepsy, autism or cortical malformations using genome-wide detection methods. Speech delay appears to be the most common manifestation. Although a variety of additional anomalies such as various mild dysmorphic facial features, cortical malformations, craniosynostosis, cleft palate and neurological problems have been described in individual patients, no recognizable phenotype for this microduplication has emerged as yet. In some reported cases the duplication was inherited from a seemingly unaffected parent, further complicating the interpretation of the clinical consequences of the chromosomal abnormality.

Screening a cohort of 300 patients with mental retardation for subtelomeric abnormalities and recurrent microdeletion/duplication syndromes using an array-based MLPA method, revealed two patients with a 7q11.23 microduplication (MLPA probes in LIMK1, GTF2IRD1, STX1A; Rooms et al., manuscript in preparation). In both patients, the duplication is inherited and no other possibly disease causing genomic rearrangement was detected. The duplications in both families are identical and involve the reciprocal of the commonly 1.45 Mb deleted interval in WBS. The first patient detected was a 12-year-old male with a history of diaphragmatic hernia, hypotonia in infancy, language delay and mild mental retardation. Both the proband and his father, who also carries the duplication, have autistic features and severe behavioural problems. The other patient was a 10-year-old male with severe intractable epilepsy and moderate mental retardation. He has always been hypotonic and his motor milestones and speech were significantly delayed. He inherited the duplication from his mother who has a history of learning difficulties. As we were unable to draw definite conclusions from the literature whether the duplication was disease causing in our patients, we collected a further 12 new 7q11.23 cases with the reciprocal duplication of the Williams–Beuren syndrome region from different centers that used various genome-wide screening methods. These include seven familial and five de novo cases in which we compared the clinical findings in a standardized way and compared those with the previously identified patients. We found that the patients have some phenotypical characteristics in common, suggestive of a clinically recognizable syndrome.

Section snippets

Patient collection and platforms used for the identification of the patients

We collected 12 probands with a submicroscopic 7q11.23 duplication and two sibs. Patients were identified through either a home made array-based MLPA, MLPA (kit p245_A1, MRC-Holland, Amsterdam, The Netherlands), the 44k or 244K Agilent oligonucleotide array (Agilent Technologies, Inc., Santa Clara, CA, USA), home made 1 Mb BAC array, Illumina Infinium CNV370 BeadChip (Illumina, Inc., San Diego, CA, USA) or the 500K Affymetrix SNP array (Affymetrix Inc., Santa Clara, CA, USA). The size of the

Molecular characterization and population frequency of the 7q11.23 duplication

All probands carried the same 1.4–1.5 Mb duplication, the reciprocal product of the WBS critical region (Fig. 1). Five cases were de novo. The other patients, including two sib pairs, carried an inherited duplication (three paternally and six maternally). The presence of additional potentially disease causing genomic rearrangements was excluded by whole genome SNP genotyping array, array-CGH or oligonucleotide array. Thirteen index patients (one patient was not included in this study), were

Discussion

We present 12 index patients and two sibs with the exact reciprocal duplication of the Williams–Beuren critical region. Our study confirms that the clinical phenotype of the 7q11.23 microduplication group is milder, less distinct and more variable than in WBS. In concordance with earlier reports, speech delay is a predominant and consistent finding among our patients. This language delay has been put in direct contrast to the fluent expressive language that is one of the most interesting

Acknowledgements

We thank the patients and their parents who participated in this study. Our work was supported by grants from the Marguerite-Marie Delacroix foundation, the Belgian National Fund for Scientific Research – Flanders (FWO), the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT), the Estonian Science foundation grant 7617, the AnEUploidy project, a sixth framework integrated project (B.v.B., B.B.A.d.V.) and grants from The Netherlands Organisation for Health

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