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

外显子组测序 生物 遗传学 产前诊断 睫状体病 人类遗传学 人口 遗传异质性 表型 胎儿 基因 怀孕 医学 环境卫生
作者
Mohamed H. Al‐Hamed,Wesam Kurdi,Rubina Khan,Maha Tulbah,Maha Alnemer,Nada Alsahan,Maisoon Almugbel,Rafiullah Rafiullah,Mirna Assoum,Dorota Monies,Zeeshan Shah,Zuhair Rahbeeni,Nada Derar,Fahad Hakami,Gawaher Almutairi,Afaf AlOtaibi,Wafaa Ali,Amal AlShammasi,Wardah AlMubarak,Samia AlDawoud,Saja AlAmri,Bashayer Saeed,Hanifa Bukhari,Mohannad Ali,Rana Akili,Laila Alquayt,Samia Hagos,Hadeel Elbardisy,Asma Akilan,Nora Almuhana,Abrar AlKhalifah,Mohamed Abouelhoda,Khushnooda Ramzan,John A. Sayer,Faiqa Imtiaz
出处
期刊:Human Genetics [Springer Nature]
卷期号:141 (1): 101-126 被引量:7
标识
DOI:10.1007/s00439-021-02406-9
摘要

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.
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