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Background <p><i>ZMYM2</i>-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 <i>ZMYM2</i>. 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.</p> Case presentation <p>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 <i>ZMYM2</i> (NM_001353162.2): c.1293_1296del (p.Thr432ArgfsTer11). Notably, the parents harbored independent skeletal dysplasia variants — <i>NPR2</i> p.Arg388Ter in the mother (consistent with proportionate short stature) and <i>FGFR3</i> p.Arg223Cys in the father (consistent with hypochondroplasia phenotype) — neither transmitted to the proband, representing co-occurring independent molecular findings within one family.</p> Conclusions <p>This case expands the mutational and phenotypic spectrum of NECRC syndrome, demonstrating that <i>ZMYM2</i> 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. <i>ZMYM2</i> deficiency should be considered as a potential cause in the differential diagnosis of neurodevelopmental disorders regardless of renal or cardiac involvement.</p>

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A novel de novo frameshift variant in ZMYM2 expands the neuropsychiatric spectrum of NECRC syndrome: a case report

  • 期刊论文

  • 发表日期：

    2026年4月29日

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  • Nurana Mammadova,
  • Nihal Hatipoglu,
  • Munis Dundar

摘要

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.