Summary 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, POMGNT1), some implicated for the first time in ASD. 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.

We studied 21 patients with Sanjad-Sakati syndrome (SSS) from 16 families. Parental consanguinity was recorded in 2 families (12.5%). All patients had severe intrauterine growth retardation, short stature, small hands and feet, blue sclera, deep-set eyes, microcephaly, persistent hypocalcaemia and hypoparathyroidism. Medullary stenosis was detected in 2 patients. Cytogenetic and fluorescent in situ hybridization studies were normal. All affected persons had homozygous deletion of 12 bp (155-166del) in exon 3 of the TBCE gene. All of the parents were heterozygous carriers of this mutation. The high frequency of SSS and low frequency of consanguineous marriages in this study may reflect a high rate of heterozygous carriers. ‫الكويت‬ ‫يف‬ ‫حالة‬

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We describe 3 sibs, two females and a male, with hypogonadism, defective Müllerian development in the sisters, and partial alopecia consisting of cranial hair only in the center of the scalp. One sister had absent gonads, the other had streak ovaries; both had markedly hypoplastic internal genitalia. Their brother had hormonal and histologic findings consistent with germinal cell aplasia. In view of the fact that the parents were consanguineous, autosomal recessive inheritance of the syndrome is likely.

A stratified representative sample size of 5,007 Kuwaiti females aged 15 years and above was drawn during 1983 and structurally interviewed to study the influence of consanguineous marriages (up to the second cousin) on reproductive wastage. Losses comprised prenatal deaths (abortions and stillbirths) and neonatal deaths (up to the first month of life). The rate of consanguineous mating in the sample was 54.3% with 95% confidence limits estimated rate 52.9% to 55.7% when projected over the whole Kuwaiti population. First cousin marriages accounted for 30.2% of the sample followed by 22.1 YO less than first cousin (first cousin once removed and second cousins) and 2% only double first cousin. The study showed higher prenatal and neonatal losses among consanguineous (l4.2%, 2.97%) than nonconsanguineous (13.97%, 2.54%) although not statistically significant. No consistent increase in reproductive wastage was evident as the inbreeding coefficient, F, advances mainly because of decline in the wastage rate among the double first cousin marriages which represents only 2% of our sample.