Understanding complex begins with knowing the simple

Abstract

Diagnosing rare genetic disorders is clinically challenging. Patients undergo extensive investigations, including multiple genetic/genomic tests. Despite being seen by several specialists, they often remain without a genetic diagnosis. A 4-year-old female with consanguineous parents presents with skeletal abnormalities, dysmorphism, global developmental delay, slow growth, and recurrent severe systemic infections. Initial next generation sequencing based primary immunodeficiency gene panel and SNP microarray detected no causative pathogenic variants. The final diagnosis was possible only following a special cytogenetic test, C-banded karyotype, which revealed heterochromatin repulsion and premature centromere separation in all metaphases, suggestive of Roberts syndrome (RS). RS/ESCO2-spectrum disorder is a rare autosomal recessive disorder caused by biallelic loss of function variants in the ESCO2 gene, with only 150 cases reported to date. Microarray analysis also showed long contiguous stretches of homozygosity at the 8p21 locus, which encompasses the ESCO2 gene. ESCO2 gene sequencing was recommended for molecular confirmation of the diagnosis. This case illustrates the importance of appropriate selection of genomic tests and highlights the critical role of karyotyping (including the use of specialized stains) in the diagnosis of some rare genetic disorders.