Background: Roberts–SC phocomelia syndrome (RBS; OMIM #268300) is a rare autosomal recessive disorder caused by biallelic variants in the sister chromatid cohesion N-acetyltransferase 2 (ESCO2) gene. It is characterized by tetraphocomelia and craniofacial anomalies. Prenatal cases are often lethal, and molecular confirmation is crucial for diagnosis and recurrence prevention. Case: We investigated a Chinese family with recurrent fetuses that presented severe tetraphocomelia. Whole-exome sequencing (WES) of both fetuses and their parents was performed, followed by Sanger validation, protein modeling using AlphaFold2, and Western blot analysis in transfected human embryonic kidney 293 (HEK293) cells. Two fetuses carried novel compound heterozygous nonsense variants in ESCO2, c.754A>T (p.Lys252*) and c.1276G>T (p.Glu426*). Structural modeling predicted truncated proteins lacking the C-terminal acetyltransferase domain. Western blot analysis showed that p.Lys252* caused complete loss of ESCO2, whereas p.Glu426* produced a truncated protein. Based on these findings, PGT-M was performed, identifying a mutation-free embryo for transfer. Prenatal testing confirmed the absence of ESCO2 variants, and a healthy child was delivered. Conclusions: We report novel ESCO2 variants associated with severe prenatal RBS and provide functional and clinical evidence supporting their pathogenicity. This study expands the ESCO2 genotype–phenotype spectrum and underscores the value of molecular diagnosis and PGT-M in preventing recurrence of lethal autosomal recessive disorders.
Wang et al. (Thu,) studied this question.