MEIS2 sequence variant in a child with intellectual disability and cardiac defects: Expansion of the phenotypic spectrum and documentation of low-level mosaicism in an unaffected parent.

Deletions and pathogenic sequence variants in Myeloid Ecotropic Insertion Site 2 (MEIS2) gene have been reported to cause a recognizable triad of intellectual disability, congenital heart malformations, and palatal defects. To date, 18 individuals with de novo pathogenic sequence variants in MEIS2 have been reported in the literature, most with all three cardinal features. We recently saw a young boy, almost 3 years of age, who was known to have mosaic XYY syndrome (47,XYY [23]/46,XY[7]). He presented with atrial and ventricular septal defects, developmental delay, facial dysmorphism, gastroesophageal reflux, undescended testicle, a buried penis with penoscrotal transposition, primary neutropenia, and a branchial cleft sinus. Whole-exome sequencing identified a previously reported in-frame pathogenic deletion (c.998_1000delGAA; p.R333del; NM_170674.4) in MEIS2. His unaffected father was confirmed to have low-level mosaicism for the same MEIS2 variant. The proband represents the 19th reported individual with a pathogenic sequence variant in MEIS2 and expands the phenotypic spectrum to include primary neutropenia, branchial anomalies, and complex genital anomalies. Furthermore, to our knowledge this is the first reported case of mosaicism for a variant in this gene in an apparently unaffected parent. This finding would have implications for recurrence risk counseling for families.