Clinical application of trio-based whole-exome sequencing in children born small for gestational age with failed catch-up growth or multisystem anomalies

Objective To evaluate the molecular diagnostic utility of trio-based whole-exome sequencing (trio-WES) in a clinically selected subgroup of children born small for gestational age (SGA) who had failed catch-up growth and/or multisystem anomalies. Methods We retrospectively studied 99 children born small for gestational age (SGA) who had failed catch-up growth and/or multisystem anomalies. Trio-WES included sequence-variant and copy-number variant (CNV) analysis. Sequence variants were confirmed by Sanger sequencing. CNVs were inferred from trio-WES read-depth data, and parental segregation was assessed from the trio sequencing data. Sequence variants and CNVs were classified using ACMG/AMP and ACMG/ClinGen standards, respectively. Only pathogenic/likely pathogenic (P/LP) findings that explained the inheritance model were counted as molecular diagnoses. Results A confirmed molecular diagnosis was established in 59 of 99 children (59.6%).4 variants were categorized as variants of uncertain significance (VUS). These diagnoses comprised monogenic disorders in 44 children (74.6%), CNVs in 13 (22.0%) and dual sequence-variant/CNV diagnoses in two (3.4%). Diagnostic yields were 52.9% (9/17) in children with isolated failed catch-up growth and 61.0% (50/82) in those with multisystem anomalies. Conclusions Trio-WES can provide a molecular diagnosis in a substantial proportion of this selected high-risk SGA subgroup. These findings support the use of trio-WES for molecular diagnosis, individualized management and genetic counselling in high-risk children born SGA.However, the diagnostic yield should not be generalized to the overall SGA population.