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Barkova E.,South Shore Regional Hospital | Mohan U.,University of Calgary | Chitayat D.,The Prenatal Diagnosis and Medical Genetics Program | Toi A.,Mount Sinai Hospital | And 4 more authors.
Clinical Genetics | Year: 2015

Fetal skeletal dysplasias are a heterogeneous group of rare genetic disorders, affecting approximately 2.4-4.5 of 10,000 births. We performed a retrospective review of the perinatal autopsies conducted between the years 2002-2011 at our center. The study population consisted of fetuses diagnosed with skeletal dysplasia with subsequent termination, stillbirth and live-born who died shortly after birth. Of the 2002 autopsies performed, 112 (5.6%) were diagnosed with skeletal dysplasia. These 112 cases encompassed 17 of 40 groups of Nosology 2010. The two most common Nosology groups were osteogenesis imperfecta [OI, 27/112 (24%)] and the fibroblast growth factor receptor type 3 (FGFR3) chondrodysplasias [27/112 (24%)]. The most common specific diagnoses were thanatophoric dysplasia (TD) type 1 [20 (17.9%)], and OI type 2 [20 (17.9%)]. The combined radiology, pathology, and genetic investigations and grouping the cases using Nosology 2010 resulted in a specific diagnosis in 96 of 112 cases. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hashemi B.,University of Toronto | Bassett A.,Clinical Genetics Research Program | Chitayat D.,University of Toronto | Chong K.,The Prenatal Diagnosis and Medical Genetics Program | And 14 more authors.
American Journal of Medical Genetics, Part A | Year: 2015

Microdeletion of the BP1-BP2 region at 15q11.2 is a recurrent copy number variant (CNV) frequently found in patients undergoing chromosomal microarray (CMA). Genetic counselling regarding this CNV is challenging due to the wide range of phenotypic presentation in reported patients and lack of general population-based data. As one of the most common reasons for CMA is childhood developmental delay, clinicians need to be cognizant of the inherent ascertainment bias in the literature. We performed a detailed medical record review for 55 patients with this 15q11.2 microdeletion and report the clinical features of the 35 patients for whom information was available. We compared our results to the recent report by Cafferkey et al. in this journal. Our conclusion is that the phenotypic spectrum is too broad and non-specific to constitute a bona fide "syndrome" and that further research must be done to delineate the contribution of this CNV to phenotype. © 2015 Wiley Periodicals, Inc.

Roifman M.,The Prenatal Diagnosis and Medical Genetics Program | Roifman M.,University of Toronto | Marcelis C.L.M.,Radboud University Nijmegen | Paton T.,Applied Genomics | And 11 more authors.
Clinical Genetics | Year: 2015

Robinow Syndrome (RS), a rare skeletal dysplasia syndrome, is characterized by dysmorphic features resembling a fetal face, mesomelic limb shortening, hypoplastic external genitalia in males, and renal and vertebral anomalies. Both autosomal dominant and autosomal recessive patterns of inheritance have been reported. Since the description of autosomal dominant Robinow Syndrome (ADRS; OMIM 180700) in 1969 by Meinhard Robinow and colleagues, the molecular etiology remained elusive until only recently. WNT5A was proposed to be the candidate gene for ADRS, as mutations were found in two affected families, one of those being the originally described index family. We report three families with RS caused by novel heterozygous WNT5A mutations, which were confirmed in the first family by whole exome sequencing, and in all by Sanger sequencing. To our knowledge, this is the largest number of published families with ADRS in whom a WNT5A mutation was identified. Families 1 and 2 are the first cases showing de novo inheritance in the affected family members and thus strengthen the evidence for WNT5A as the causative gene in ADRS. Finally, we propose WNT5A mutation specificity in ADRS, which may affect interactions with other proteins in the Wnt pathway. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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