The wide variety in incidence rates of neural tube defects (NTD) in the Arabian region have been attributed to environmental, dietary and genetic factors. No previous study has been conducted in the State of Qatar to document the incidence and trends of NTD. The aim of this study is to determine the incidence and trends of NTD over a period of 25 yr in the State of Qatar. This is a retrospective hospital based cohort study. The survey was carried out in the main territory hospital in the State of Qatar. The study was conducted from 1985 to 2009 with a total of 302,049 newborns at the Women's Hospital in Qatar screened for NTD. NTD were defined according to the International Classification of Diseases, Tenth Revision. Study parameters included age, gender, ethnicity, parental consanguinity, and residential area. The combined prevalence of NTD (total myelomeningocele and anencephaly) during the 25 yr period was 1.09 per 1,000 births. The prevalence of anencephaly was 0.36 per 1,000 births. There were 131 (42.1%) males and 180 (57.9%) female newborns with NTD, corresponding to incidence of 0.899 and 1.289 per 1,000 in male and female newborns, respectively. This difference was significant (P <0.001). Consanguinity was seen in 36.7% of the parents. The present study revealed that Qatar has a relatively low incidence of NTD, which is comparable to neighboring countries in the Arabian Gulf region. High rates of consanguinity and lack of periconceptual folic acid intake among mothers appear to be the major factors contributing to NTD in Qatar.

Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.

Hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome [also known as Woodhouse–Sakati syndrome (WSS)] is a rare autosomal recessive neuroendocrine and ectodermal disorder. The syndrome was first described by Woodhouse and Sakati in 1983, and 47 patients from 23 families have been reported so far. We report on an additional seven patients (four males and three females) from two highly consanguineous Arab families from Qatar, presenting with a milder phenotype of WSS. These patients show the spectrum of clinical features previously found in WSS, but lack evidence of diabetes mellitus and extrapyramidal symptoms. These two new families further illustrate the natural course and the interfamilial phenotypic variability of WSS that may lead to challenges in making the diagnosis. In addition, our study suggests that WSS may not be as infrequent in the Arab world as previously thought. © 2011 Wiley Periodicals, Inc.

Van Den Ende-Gupta syndrome (VDEGS) is an infrequently described disorder characterized by arachnodactyly, camptodactyly, blepharophimosis, malar hypoplasia, narrow nasal bridge, convex nasal ridge, and everted lower lip. Patients show normal growth and cognition. We report on three male and three female cases from four consanguineous families, of which three belong to the same highly inbred tribe from Qatar. The phenotype in the patients is remarkably homogeneous. VDEGS has been suggested both to follow an autosomal recessive and autosomal dominant pattern of inheritance, but our observations suggest an autosomal recessive pattern of inheritance, although genetic heterogeneity cannot be excluded.

Van Den Ende-Gupta syndrome (VDEGS) is an extremely rare autosomal-recessive disorder characterized by distinctive craniofacial features, which include blepharophimosis, malar and/or maxillary hypoplasia, a narrow and beaked nose, and an everted lower lip. Other features are arachnodactyly, camptodactyly, peculiar skeletal abnormalities, and normal development and intelligence. We present molecular data on four VDEGS patients from three consanguineous Qatari families belonging to the same highly inbred Bedouin tribe. The patients were genotyped with SNP microarrays, and a 2.4 Mb homozygous region was found on chromosome 22q11 in an area overlapping the DiGeorge critical region. This region contained 44 genes, including SCARF2, a gene that is expressed during development in a number of mouse tissues relevant to the symptoms described above. Sanger sequencing identified a missense change, c.773G>A (p.C258Y), in exon 4 in the two closely related patients and a 2 bp deletion in exon 8, c.1328_1329delTG (p.V443DfsX83), in two unrelated individuals. In parallel with the candidate gene approach, complete exome sequencing was used to confirm that SCARF2 was the gene responsible for VDEGS. SCARF2 contains putative epidermal growth factor-like domains in its extracellular domain, along with a number of positively charged residues in its intracellular domain, indicating that it may be involved in intracellular signaling. However, the function of SCARF2 has not been characterized, and this study reports that phenotypic effects can be associated with defects in the scavenger receptor F family of genes.

The oral-facial-digital syndrome type I (OFD I) is characterized by multiple congenital malformations of the face, oral cavity and digits. A polycystic kidney disease (PKD) is found in about one-third of patients but long-term outcome and complications are not well described in the international literature. Renal findings have been retrospectively collected in a cohort of 34 females all carrying a pathogenic mutation in the OFD1 gene with ages ranging from 1 to 65 years. Twelve patients presented with PKD - 11/16 (69%) if only adults were considered -with a median age at diagnosis of 29 years [IQR (interquartile range) = (23.5-38)]. Among them, 10 also presented with renal impairment and 6 were grafted (median age = 38 years [IQR = (25-48)]. One grafted patient under immunosuppressive treatment died from a tumor originated from a native kidney. The probability to develop renal failure was estimated to be more than 50% after the age of 36 years. Besides, neither genotype-phenotype correlation nor clinical predictive association with renal failure could be evidenced. These data reveal an unsuspected high incidence rate of the renal impairment outcome in OFD I syndrome. A systematic ultrasound (US) and renal function follow-up is therefore highly recommended for all OFD I patients.

Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disorder in which patients display tortuosity of arteries in addition to hyperextensible skin, joint laxity, and other connective tissue features. This syndrome is caused by mutations in the SLC2A10 gene. In this article we describe an ATS girl of Kurdish origin who, in addition to arterial tortuosity and connective tissue features, displays stomach displacement within the thorax and bilateral hip dislocation. Clinical details of this patient have been reported previously. Sequencing of the SLC2A10 gene identified a novel homozygous non-sense c.756C>A mutation in this patient's DNA. This mutation in the SLC2A10 gene replaces a cysteine encoding codon with a stop signal. This is believed to cause a premature truncation of GLUT10 protein in this patient. We conclude that patients of Kurdish origin who display arterial tortuosity associated with skin hyperextensibility, joint hypermobility, and characteristic facial features may carry mutations in the SLC2A10 gene.

BACKGROUND:Many epidemiological studies have indicated that inbreeding has little or no effect on the incidence of cancer. Due to the high prevalence of consanguinity in Qatar (54%), its influence may nevertheless be of special importance.AIM:The aim of this study was to examine whether parental consanguinity affects the risk of cancer in a local Arab highly inbred population.DESIGN:Matched case-control study.SETTING:The study was carried out in Al-Amal cancer hospital and primary health care centers in Qatar over a period from August 2008 to February 2009.SUBJECTS AND METHODS:The study included 370 Qataris and other Arab expatriates with various types of cancers and 635 controls matched by age and ethnicity. A questionnaire that included socio-demographic information, type of consanguinity, medical history, and tumor grade was designed to collect the information of cases and controls.RESULTS:The study revealed that the rate of parental consanguinity was similar in both cases (29.5%) and controls (29.9%) with a higher inbreeding coefficient in controls (0.017-/+0.03), compared to cancer patients (0.0155-/+0.03). Other Arab expatriates had a higher incidence of cancer (61.1%) than Qataris (38.9%). The inbreeding coefficient was higher in male cancer patients (0.0189-/+0.03), but lower in female cancer patients (0.014-/+0.03) as compared to controls. Controls were more inbred in the overall studied subjects (23.6%) and women (23.8%) than cases. The coefficient of inbreeding was lower in patients with breast (0.014), skin (0.012), thyroid (0.008) and female genital (0.014) cancers, whereas it was higher in cases for leukemia and lymphoma (0.018), colorectal (0.025) and prostate (0.017), with no significant difference between cases and controls. No significant differences were observed between cases and controls in the parental consanguinity, mean coefficient of inbreeding and proportion of more inbred subjects.CONCLUSIONS:The study findings revealed that although the consanguinity rate is high in our Arab population, it has no effect on the incidence of cancers overall. However, there was an increased risk found for leukemia and lymphoma, colorectal and prostate cancer groups, but a reduced risk in breast, skin, thyroid and female genital cancer groups.

Clinical GeneticsVolume 75, Issue 6 p. 588-589 Congenital diaphragmatic abnormalities in arterial tortuosity syndrome patients who carry mutations in the SLC2A10 gene SHE Zaidi, Corresponding Author SHE Zaidi Division of Cardiology, Department of Medicine, University Health Network, Toronto, Ontario, CanadaSyed HE ZaidiDivision of CardiologyDepartment of MedicineUniversity Health Network101 College StreetTMDT East TowerRoom 3-910TorontoOntario M5G 1L7CanadaTel.: 416 581-7491Fax: 1-416 581-7489e-mail: [email protected]Search for more papers by this authorS Meyer, S Meyer Universitaetsklinikum des Saarlandes, Kirrberger Strasse, Homburg, GermanySearch for more papers by this authorI Peltekova, I Peltekova Department of Medicine, Queens University, Kingston, Ontario, CanadaSearch for more papers by this authorAS Teebi, AS Teebi Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar Department of Pediatrics, Weill Cornell Medical College, Doha, Qatar Section of Clinical Genetics and Dysmorphology, Hospital for Sick Children, Toronto, Ontario, CanadaSearch for more papers by this authorM Faiyaz-Ul-Haque, M Faiyaz-Ul-Haque Molecular Genetics Laboratory, Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Department of Genetics, College of Medicine, Alfaisal University, Riyadh, Saudi ArabiaSearch for more papers by this author SHE Zaidi, Corresponding Author SHE Zaidi Division of Cardiology, Department of Medicine, University Health Network, Toronto, Ontario, CanadaSyed HE ZaidiDivision of CardiologyDepartment of MedicineUniversity Health Network101 College StreetTMDT East TowerRoom 3-910TorontoOntario M5G 1L7CanadaTel.: 416 581-7491Fax: 1-416 581-7489e-mail: [email protected]Search for more papers by this authorS Meyer, S Meyer Universitaetsklinikum des Saarlandes, Kirrberger Strasse, Homburg, GermanySearch for more papers by this authorI Peltekova, I Peltekova Department of Medicine, Queens University, Kingston, Ontario, CanadaSearch for more papers by this authorAS Teebi, AS Teebi Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar Department of Pediatrics, Weill Cornell Medical College, Doha, Qatar Section of Clinical Genetics and Dysmorphology, Hospital for Sick Children, Toronto, Ontario, CanadaSearch for more papers by this authorM Faiyaz-Ul-Haque, M Faiyaz-Ul-Haque Molecular Genetics Laboratory, Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Department of Genetics, College of Medicine, Alfaisal University, Riyadh, Saudi ArabiaSearch for more papers by this author First published: 01 June 2009 https://doi.org/10.1111/j.1399-0004.2009.01165.xCitations: 5Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume75, Issue6June 2009Pages 588-589 RelatedInformation

Mutations in the angiopoietin receptor TIE2/TEK have been identified as the cause for autosomal dominantly inherited cutaneomucosal venous malformation (VMCM). Thus far, two specific germline substitutions (R849W and Y897S), located in the kinase domain of TIE2, have been reported in five families. The mutations result in a fourfold increase in ligand-independent phosphorylation of the receptor. Here, we report 12 new families with TEK mutations. Although the phenotype is primarily characterized by small multifocal cutaneous vascular malformations, many affected members also have mucosal lesions. In addition, cardiac malformations are observed in some families. Six of the identified mutations are new, with three located in the tyrosine kinase domain, two in the kinase insert domain, and another in the carboxy terminal tail. The remaining six are R849W substitutions. Overexpression of the new mutants resulted in ligand-independent hyperphosphorylation of the receptor, suggesting this is a general feature of VMCM-causative TIE2 mutations. Moreover, variation in the level of activation demonstrates, to the best of our knowledge for the first time, that widely differing levels of chronic TIE2 hyperphosphorylation are tolerated in the heterozygous state, and are compatible with normal endothelial cell function except in the context of highly localized areas of lesion pathogenesis.

Interstitial deletions involving 6q11-q14 have been reported in less than 20 patients, with the breakpoints studied by G-banding alone. We report on seven patients with 6q11-q14 interstitial deletions of variable size. The breakpoints were studied by G-banding, dual-color BAC-FISH and SNP array. The results showed the molecular breakpoints differed significantly from the ones obtained from G-banding. The breakpoints studied by BAC-FISH were consistent with the ones from SNP array. Some characteristics from this cohort are consistent with previous reports, but many typical features are lacking in our patients. The cardinal features of 6q11-q14 interstitial deletions in this cohort include: umbilical hernia, hypotonia, short stature, characteristic facial features of upslanting palpebral fissures, low set and/or dysplastic ears, high arched palate, urinary tract anomalies, and skeletal/limb anomalies.

Oral-facial-digital type I syndrome (OFDI) is characterised by an X-linked dominant mode of inheritance with lethality in males. Clinical features include facial dysmorphism with oral, dental and distal abnormalities, polycystic kidney disease and central nervous system malformations. Considerable allelic heterogeneity has been reported within the OFD1 gene, but DNA bi-directional sequencing of the exons and intron-exon boundaries of the OFD1 gene remains negative in more than 20 % of cases. We hypothesized that genomic rearrangements could account for the majority of the remaining undiagnosed cases. Thus, we took advantage of two independent available series of patients with OFDI syndrome and negative DNA bi-directional sequencing of the exons and intron-exon boundaries of the OFD1 gene from two different European labs: 13/36 cases from the French lab; 13/95 from the Italian lab. All patients were screened by a semiquantitative fluorescent multiplex method (QFMPSF) and relative quantification by real-time PCR (qPCR). Six OFD1 genomic deletions (exon 5, exons 1-8, exons 1-14, exons 10-11, exons 13-23 and exon 17) were identified, accounting for 5 % of OFDI patients and for 23 % of patients with negative mutation screening by DNA sequencing. The association of DNA direct sequencing, QFMPSF and qPCR detects OFD1 alteration in up to 85 % of patients with a phenotype suggestive of OFDI syndrome. Given the average percentage of large genomic rearrangements (5 %), we suggest that dosage methods should be performed in addition to DNA direct sequencing analysis to exclude the involvement of the OFD1 transcript when there are genetic counselling issues. (C) 2008 Wiley-Liss, Inc.