Genetic basis of neurodevelopmental disorders in 103 Jordanian families.

We recruited 103 families from Jordan with neurodevelopmental disorders (NDD) and patterns of inheritance mostly suggestive of autosomal recessive inheritance. In each family, we investigated at least one affected individual using exome sequencing and an in-house diagnostic variant interpretation pipeline including a search for copy number variation. This approach led us to identify the likely molecular defect in established disease genes in 37 families. We could identify 25 pathogenic nonsense and 11 missense variants as well as 3 pathogenic copy number variants and 1 repeat expansion. Notably, 11 of the disease-causal variants occurred de novo. In addition, we prioritized a homozygous frameshift variant in PUS3 in two sisters with intellectual disability. To our knowledge, PUS3 has been postulated only recently as a candidate disease gene for intellectual disability in a single family with three affected siblings. Our findings provide additional evidence to establish loss of PUS3 function as a cause of intellectual disability.

Diagnostic exome sequencing to elucidate the genetic basis of likely recessive disorders in consanguineous families.

Rare, atypical, and undiagnosed autosomal-recessive disorders frequently occur in the offspring of consanguineous couples. Current routine diagnostic genetic tests fail to establish a diagnosis in many cases. We employed exome sequencing to identify the underlying molecular defects in patients with unresolved but putatively autosomal-recessive disorders in consanguineous families and postulated that the pathogenic variants would reside within homozygous regions. Fifty consanguineous families participated in the study, with a wide spectrum of clinical phenotypes suggestive of autosomal-recessive inheritance, but with no definitive molecular diagnosis. DNA samples from the patient(s), unaffected sibling(s), and the parents were genotyped with a 720K SNP array. Exome sequencing and array CGH (comparative genomic hybridization) were then performed on one affected individual per family. High-confidence pathogenic variants were found in homozygosity in known disease-causing genes in 18 families (36%) (one by array CGH and 17 by exome sequencing), accounting for the clinical phenotype in whole or in part. In the remainder of the families, no causative variant in a known pathogenic gene was identified. Our study shows that exome sequencing, in addition to being a powerful diagnostic tool, promises to rapidly expand our knowledge of rare genetic Mendelian disorders and can be used to establish more detailed causative links between mutant genotypes and clinical phenotypes.

Jordan: communities and community genetics.

The population in Jordan mounted from half a million in 1952 to 5.3 millions in 2004 and is composed of a variety of ethnic groups, the majority being Arabs. Couples nowadays tend to have fewer children, with the total fertility rate falling from 7.4 in 1976 to 3.7 in 2004. Consanguineous marriages are traditionally favored, with the preferred marriage partner being the offspring of the father's brother. First-cousin marriages declined from 28.5% for marriages contracted between 1950 and 1979 to 19.5% for marriages contracted after 1980. In the overall population, carrier rates for beta-thalassemia, alpha-thalassemia and sickle cell anemia are in the range of 2-4%, 3.2-12% of males have glucose-6-phosphate dehydrogenase deficiency, and the prevalences for familial Mediterranean fever and cystic fibrosis were estimated at around 0.04% each. A mandatory premarital screening program for beta-thalassemia carriers commenced in June 2004. The high consanguinity rate and the large family size in Jordan have contributed to the description of a number of rare and new autosomal recessive conditions. Genetic services in Jordan are still scarce and do not cover all the country due to the major impediments of a paucity of resources and trained health professionals in the area of medical genetics. The demographic data suggest that the health system in Jordan is capable of introducing some basic community genetic services into the primary health care program through comprehensive and cost-effective programs.