Heterozygous CECR2 variants support a distinct neurodevelopmental syndrome with features overlapping cat eye syndrome.

The CECR2 histone acetyl-lysine reader facilitates chromatin remodeling and plays a significant role in neurodevelopment. It resides within the cat eye syndrome (CES) critical region at 22q11.1q11.21. An increased copy number of this region, often as tetrasomy or a supernumerary chromosome, results in CES. The complex chromosomal arrangements and phenotypic variability have hampered the identification of the true cause(s) of CES. Patients and their clinical data were collected from multiple diagnostic and research laboratories. Exome or genome sequencing was performed in affected individuals and, when available, their relatives. Here, we describe six patients with a heterozygous single-nucleotide or small insertion/deletion variant in CECR2 and their clinical features. Variants were either loss-of-function [c.1734dupC:p.(Thr580Hisfs∗98), c.1819C>T:p.(Arg607∗), and c.2281C>T:p.(Arg761∗)] or missense in an intrinsically disordered and potentially critical region at the C terminus of the protein [c.4153C>G:p.(Gln1385Glu), c.4254C>G:p.(Phe1418Leu), and c.4283A>G:p.(Gln1428Arg)]. The main clinical features were delayed growth, relatively small head circumference, developmental delay, and speech issues/delay. Other clinical findings were variable and included intellectual disability; feeding problems; facial dysmorphism; cleft lip/palate; brain, ear, heart, or other organ abnormalities; behavioral abnormalities; and epilepsy. There was significant overlap with common CES features, including ear, heart, and brain abnormalities, intellectual disability, and growth restriction. In conclusion, we characterize a CECR2-associated neurodevelopmental disorder. The consistent molecular and clinical overlap with CES supports CECR2's role in the CES phenotype. These findings implicate diverse variant types in related neurodevelopmental disorders, underscoring CECR2's dosage sensitivity and essential function in epigenetic regulation during development.