Prenatal exome sequencing and chromosomal microarray analysis in fetal structural anomalies in a highly consanguineous population reveals a propensity of ciliopathy genes causing multisystem phenotypes.

Fetal abnormalities are detected in 3% of all pregnancies and are responsible for approximately 20% of all perinatal deaths. Chromosomal microarray analysis (CMA) and exome sequencing (ES) are widely used in prenatal settings for molecular genetic diagnostics with variable diagnostic yields. In this study, we aimed to determine the diagnostic yield of trio-ES in detecting the cause of fetal abnormalities within a highly consanguineous population. In families with a history of congenital anomalies, a total of 119 fetuses with structural anomalies were recruited and DNA from invasive samples were used together with parental DNA samples for trio-ES and CMA. Data were analysed to determine possible underlying genetic disorders associated with observed fetal phenotypes. The cohort had a known consanguinity of 81%. Trio-ES led to diagnostic molecular genetic findings in 59 fetuses (with pathogenic/likely pathogenic variants) most with multisystem or renal abnormalities. CMA detected chromosomal abnormalities compatible with the fetal phenotype in another 7 cases. Monogenic ciliopathy disorders with an autosomal recessive inheritance were the predominant cause of multisystem fetal anomalies (24/59 cases, 40.7%) with loss of function variants representing the vast majority of molecular genetic abnormalities. Heterozygous de novo pathogenic variants were found in four fetuses. A total of 23 novel variants predicted to be associated with the phenotype were detected. Prenatal trio-ES and CMA detected likely causative molecular genetic defects in a total of 55% of families with fetal anomalies confirming the diagnostic utility of trio-ES and CMA as first-line genetic test in the prenatal diagnosis of multisystem fetal anomalies including ciliopathy syndromes.

New susceptibility locus for obesity and dyslipidaemia on chromosome 3q22.3.

BACKGROUND: The muscle Ras (MRAS) gene resides on chromosome 3q22.3 and encodes a member of the membrane-associated Ras small GTPase proteins, which function as signal transducers in multiple processes including cell growth and differentiation. Its role in cardiovascular disease is not fully understood yet. In a preliminary study in heterozygous familial hypercholesterolaemia, we identified a locus linking the early onset of coronary artery disease (CAD) to chromosome 3q.22 and elected to sequence the MRAS gene using the MegaBACE DNA analysis system. In the present study, we investigated the association of seven single-nucleotide polymorphisms (SNPs) at this locus with CAD and its dyslipidaemia-related risk traits in 4,650 Saudi angiographed individuals using TaqMan assays by the Applied Biosystems real-time Prism 7900HT Sequence Detection System. RESULTS: Among the studied SNPs, rs6782181 (p = 0.017) and rs9818870T (p = 0.009) were associated with CAD following adjustment for sex, age and other confounding risk factors. The rs6782181_GG also conferred risk for obesity (1,764 cases vs. 2,586 controls) [1.16(1.03-1.30); p = 0.017], hypercholesterolaemia (1,686 vs. 2,744) [1.23(1.02-1.47); p = 0.019], hypertriglyceridaemia (1,155 vs. 3,496) [1.29(1.01-1.45); p = 0.043] and low high-density lipoprotein-cholesterol (lHDL-chol) levels (1,935 vs. 2,401) [1.15(1.02-1.30); p = 0.023] after adjustment. Additionally, rs253662_(CT+TT) [1.16(1.01-1.32); p = 0.030] was associated with lHDL-chol levels. Interestingly, rs253662 (p = 0.014) and rs6782181 (p = 0.019) were protective against acquiring high low-density lipoprotein-cholesterol (hLDL-chol) levels (p = 0.014), while rs1720819 showed similar effects against CAD (p < 0.0001). More importantly, a 7-mer haplotype, ACCTGAC (χ2 = 7.66; p = 0.0056), constructed from the studied SNPs, its 6-mer derivative CCTGAC (χ2 = 6.90; p = 0.0086) and several other shorter derivatives conferred risk for obesity. hLDL-chol was weakly linked to CTAA (χ2 = 3.79; p = 0.052) and CCT (χ2 = 4.32; p = 0.038), while several other haplotypes were protective against both obesity and hLDL-chol level. CONCLUSION: Our results demonstrate that the genomic locus for the MRAS gene confers risk for CAD, obesity and dyslipidaemia and point to the possible involvement of other genes or regulatory elements at this locus, rather than changes in the M-Ras protein function, in these events.