Burden of Mendelian disorders in a large Middle Eastern biobank.

BACKGROUND: Genome sequencing of large biobanks from under-represented ancestries provides a valuable resource for the interrogation of Mendelian disease burden at world population level, complementing small-scale familial studies. METHODS: Here, we interrogate 6045 whole genomes from Qatar-a Middle Eastern population with high consanguinity and understudied mutational burden-enrolled at the national Biobank and phenotyped for 58 clinically-relevant quantitative traits. We examine a curated set of 2648 Mendelian genes from 20 panels, annotating known and novel pathogenic variants and assessing their penetrance and impact on the measured traits. RESULTS: We find that 62.5% of participants are carriers of at least 1 known pathogenic variant relating to recessive conditions, with homozygosity observed in 1 in 150 subjects (0.6%) for which Peninsular Arabs are particularly enriched versus other ancestries (5.8-fold). On average, 52.3 loss-of-function variants were found per genome, 6.5 of which affect a known Mendelian gene. Several variants annotated in ClinVar/HGMD as pathogenic appeared at intermediate frequencies in this cohort (1-3%), highlighting Arab founder effect, while others have exceedingly high frequencies (> 5%) prompting reconsideration as benign. Furthermore, cumulative gene burden analysis revealed 56 genes having gene carrier frequency > 1/50, including 5 ACMG Tier 3 panel genes which would be candidates for adding to newborn screening in the country. Additionally, leveraging 58 biobank traits, we systematically assess the impact of novel/rare variants on phenotypes and discover 39 candidate large-effect variants associating with extreme quantitative traits. Furthermore, through rare variant burden testing, we discover 13 genes with high mutational load, including 5 with impact on traits relevant to disease conditions, including metabolic disorder and type 2 diabetes, consistent with the high prevalence of these conditions in the region. CONCLUSIONS: This study on the first phase of the growing Qatar Genome Program cohort provides a comprehensive resource from a Middle Eastern population to understand the global mutational burden in Mendelian genes and their impact on traits in seemingly healthy individuals in high consanguinity settings.

Postnatal Growth and Prevalence of Obesity in Infants Born Large-for-Gestational Age during the First 3 years of Life: Personal Experience and Exploration of Current Literature.

AIMS OF THE STUDY: We evaluated the growth patterns in a cohort of infants (n = 120) born large-for-gestational-age (LGA) [birth weight (Bwt) > 4 kg] from birth to age 3 years of age in comparison with normal age and sex-matched children (WHO). RESULTS: LGA infants had high weight for age Z score (WAZ) at birth that decreased significantly during the first 6 months of life (by a mean of - 0.67 SD) that was followed by significant gain during the following 6 months of life (around + 0.4 SD). These children grew on a higher centile of WAZ with no significant change during the second and third years of life.  The prevalence of obesity (WAZ > 2) increased markedly from 24% at the end of their first year to 34% and 36% at the end of their second and third years of life, respectively.  The mean length for age Z score (LAZ) decreased significantly during the first 6 months (by a mean of -0.9 SD) but was maintained at high centile (> 1 SD) during the second and 3rd years.  The weight for length SDS (WLZ) increased significantly during the first 18 months of life and decreases gradually during the second half of the 2nd year and the 3rd year.   Their head circumference SDS decreased significantly in the first 6 months and then sustained around the 70th centiles (+1 SD) in the following 18 months. CONCLUSION: Our study showed that in LGA babies obesity increased progressively after the first year of life to reach 36% at the end of the third year. Therefore, it is important to apply the early nutritional intervention to decrease the occurrence of obesity and reduce later cardiometabolic risks.

A systematic review on the genetics of male infertility in the era of next-generation sequencing.

OBJECTIVES: To identify the role of next-generation sequencing (NGS) in male infertility, as advances in NGS technologies have contributed to the identification of novel genes responsible for a wide variety of human conditions and recently has been applied to male infertility, allowing new genetic factors to be discovered. MATERIALS AND METHODS: PubMed was searched for combinations of the following terms: 'exome', 'genome', 'panel', 'sequencing', 'whole-exome sequencing', 'whole-genome sequencing', 'next-generation sequencing', 'azoospermia', 'oligospermia', 'asthenospermia', 'teratospermia', 'spermatogenesis', and 'male infertility', to identify studies in which NGS technologies were used to discover variants causing male infertility. RESULTS: Altogether, 23 studies were found in which the primary mode of variant discovery was an NGS-based technology. These studies were mostly focused on patients with quantitative sperm abnormalities (non-obstructive azoospermia and oligospermia), followed by morphological and motility defects. Combined, these studies uncover variants in 28 genes causing male infertility discovered by NGS methods. CONCLUSIONS: Male infertility is a condition that is genetically heterogeneous, and therefore remarkably amenable to study by NGS. Although some headway has been made, given the high incidence of this condition despite its detrimental effect on reproductive fitness, there is significant potential for further discoveries.