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

BackgroundFetal 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. MethodsIn 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. ResultsThe cohort had a known consanguinity of 81%. Trio-ES led to diagnostic molecular genetic ndings 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. ConclusionPrenatal trio-ES and CMA detected likely causative molecular genetic defects in a total of 55% of families with fetal anomalies con rming the diagnostic utility of trio-ES and CMA as rst line genetic test in the prenatal diagnosis of multisystem fetal anomalies including ciliopathy syndromes.Recently, a large study, which included ES in 610 fetuses with structural anomalies detected by fetal USS resulted in a diagnostic yield of 12.4%, including variants of unknown signi cance (Lord et al. 2019) while another similar-sized investigation resulted in a detection rate of 10% (Petrovski et al. 2019). The e ciency of trio-ES over solo-ES is widely accepted and the implementation of trio-ES in prenatal diagnosis leads to a higher detection rate (Dillon et al. 2018;Jelin and Vora 2018).

Extensive Phenotypic Variability in Syndrome Dysmorphic Facies, Renal Agenesis, Ambiguous Genitalia, Microcephaly, Polydactyly, and Lissencephaly (DREAM-PL): A Case Report Highlighting Diagnostic and Management Challenges

“…CTU2 is one of the two cytosolic t-RNA thiouridylase proteins, the other being CTU1, which was initially identified in a genome-wide screen for "mutator" genes in Caenorhabditis elegans ( C. elegans ) [ 1 ]. Mutator genes get their name from the fact that their mutations produce genomic instability, which boosts mutagenesis [ 2 ].…”

“…DREAM-PL syndrome is inherited in an autosomal recessive manner. The mutation that causes the syndrome can be traced back to the CTU2 gene [ 1 ]. The degree of DREAM-PL syndrome symptoms can range from mild to severe, and its clinical characteristics are highly variable.…”

“…The degree of DREAM-PL syndrome symptoms can range from mild to severe, and its clinical characteristics are highly variable. Some patients may have all the defining traits, while others may not [ 1 ]. CTU2 gene mutation causes variable brain, cardiac, and skeletal anomalies.…”

“…The acronym DREAM-PL syndrome is mainly characterized by a combination of congenital anomalies which include dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly, and lissencephaly. There are other features seen in association with this gene that may present and lead to significant morbidity to the patient, including congenital heart defects such as atrial and ventricular septal defects, patent ductus arteriosus, and hypoplastic right ventricles, hypotonia, seizures, corpus callosum agenesis/dysgenesis, narrow forehead, depressed nasal bridge and hypoplastic maxilla, micrognathia, contractures of joints of the upper and lower extremities, bilateral talipes equinovarus, and micropenis [ 1 ].…”

“…Unfortunately, there is no definitive treatment available currently for DREAM-PL syndrome besides supportive treatment. Other lines of treatment like surgical correction of birth defects can sometimes be beneficial to these patients [ 1 ].…”