Novel SNRPE-related spliceosomopathy characterized by microcephaly and congenital atrichia

Heterozygous variants in SNRPE are associated with hereditary hypotrichosis simplex and have also been reported in one case of non-syndromic microcephaly. SNRPE encodes a core protein of the pre-mRNA processing spliceosome. The disease mechanism is loss of function resulting in widespread mRNA splicing alterations. Here we report a patient with a novel blended phenotype of microcephaly and congenital atrichia due to a de novo intronic SNRPE deletion, c.82-28_82-16del, which results in exon skipping. In addition, we compare the phenotypic spectrum of patients with SNRPE-related disease with other Splicesosomopathies. Trio exome sequencing revealed a de novo intronic deletion in SNRPE (NM_003094.4) in an individual referred for microcephaly and hypotrichosis. We assessed the effect of the variant using cDNA sequencing. Our patient presented with congenital atrichia with absent brows and eye lashes, microcephaly, developmental delays, micrognathia, anteverted and prominent ears, cleft palate, conductive hearing loss with hypoplastic semicircular canal, ectopic kidney, ventricular septal defect, and bilateral thumb anomaly. We identified a de novo intronic deletion in SNRPE, c.82-28_82-16del. cDNA sequencing demonstrated skipping of exon 3 (p.Arg28_Ile48del), removing >20% of the protein. Loss of function variants in SNRPE can cause a novel syndromic form of microcephaly associated with congenital atrichia and other anomalies including micrognathia, cleft palate and digital anomaly as noted in this case report.