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

Abstract

Background 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. Methods 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. Results 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 4 fetuses. A total of 23 novel variants predicted to be associated with the phenotype were detected. Conclusion 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.

Fetal phenotypes of Mendelian disorders: A descriptive study from India

“…Majority of fetuses (87%) had an autosomal recessive disorder, 95% of these harboring a homozygous variant, which is reflective of our endogamous population structure. Similar preponderance of autosomal recessive diseases have been reported in other studies from consanguineous cohorts 7,10 . This is in contrast to reports from Caucasian population where autosomal dominant disorders constitute at least half of the diagnoses 1,3‐5,8,14 .…”

“…Al‐Hamed et al. have also reported 40.7% ciliopathies in 59 fetuses with Mendelian diseases from a study sample with 81% consanguinity where recessive conditions predominated 7 . 54% variants were novel in our cohort.…”

“…Different studies have utilized varied patient cohorts, some including ultrasonically detected fetal abnormalities, while others have included fetuses after postmortem evaluation. Diagnostic yields have also been variable, and some factors associated with higher yields are selective cohorts, consanguineous populations, and depth of phenotyping 1‐14 . Yields from larger studies involving prenatal ultrasound detected miscellaneous abnormalities with no specific selection criteria have been relatively lower 3,4 .…”

“…Exome sequencing (ES) technology is increasingly being used in both research and clinical settings to interrogate morphologically abnormal, cytogenetically normal fetuses. These studies have revealed a significant contribution of Mendelian or single gene disorders to fetal abnormalities 1‐14 . Different studies have utilized varied patient cohorts, some including ultrasonically detected fetal abnormalities, while others have included fetuses after postmortem evaluation.…”

“…Diagnostic yields have also been variable, and some factors associated with higher yields are selective cohorts, consanguineous populations, and depth of phenotyping. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] Yields from larger studies involving prenatal ultrasound detected miscellaneous abnormalities with no specific selection criteria have been relatively lower. 3,4 One of the major challenges faced in the diagnosis of fetal Mendelian disorders has been the lack of information regarding the fetal phenotypes of this group of conditions.…”