Mol Biol Rep. 2026 Apr 29;53(1):690. doi: 10.1007/s11033-026-11841-8.
ABSTRACT
BACKGROUND: ZMYM2-related neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities (NECRC; OMIM #619522) is an ultra-rare autosomal dominant condition caused by heterozygous loss-of-function (LoF) variants in ZMYM2. Since its initial description in 2020, the phenotypic spectrum has expanded to include Rett-like features and cortical myoclonus, with an increasing number of cases presenting without renal or cardiac involvement.
CASE PRESENTATION: We report a 6-year-old Turkish boy presenting with intellectual disability, attention-deficit/hyperactivity disorder (ADHD), motor stereotypies, and short stature. Psychometric evaluation revealed developmental levels of 2-2.5 years across all domains. Dysmorphic features included microcephaly, bilateral epiblepharon, pectus excavatum, bilateral pes planus, and fifth-finger clinodactyly. Renal and cardiac findings were absent. Trio whole-exome sequencing (WES) identified a novel de novo heterozygous frameshift variant in ZMYM2 (NM_001353162.2): c.1293_1296del (p.Thr432ArgfsTer11). Notably, the parents harbored independent skeletal dysplasia variants - NPR2 p.Arg388Ter in the mother (consistent with proportionate short stature) and FGFR3 p.Arg223Cys in the father (consistent with hypochondroplasia phenotype) - neither transmitted to the proband, representing co-occurring independent molecular findings within one family.
CONCLUSIONS: This case expands the mutational and phenotypic spectrum of NECRC syndrome, demonstrating that ZMYM2 LoF can present with predominant neuropsychiatric features - including ADHD and motor stereotypies - in the absence of congenital anomalies of the kidney and urinary tract (CAKUT). Trio-WES proved essential in molecularly dissecting a complex multigenic family background. ZMYM2 deficiency should be considered as a potential cause in the differential diagnosis of neurodevelopmental disorders regardless of renal or cardiac involvement.
PMID:42053849 | DOI:10.1007/s11033-026-11841-8