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A case of Neurodevelopmental-Craniofacial Syndrome with Variable Renal and Cardiac Abnormalities due to a de novo heterozygous ZMYM2 pathogenic variant. 

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction
ZMYM2 is a largely unstudied gene that appears to contribute to DNA regulation and epigenetic expression. Neurodevelopmental-Craniofacial syndrome with Variable Renal and Cardiac Abnormalities (NECRC) is a rare genetic disorder with autosomal dominant inheritance caused by pathogenic variants in ZMYM2. To our knowledge, currently only 20 individuals with this disorder have been reported in formal case reports. It is characterized by: a range of congenital anomalies of the kidney and urinary tract; heart defects; neurological manifestations, such as delayed development and autism spectrum disorder; and broad non-specific facial dysmorphisms.

 

Case Presentation
The proband is a 12-year-old male with severe visual impairment due to bilateral colobomas diagnosed at 1 year old and a complex neurologic and psychologic history. Type 1 Chiari malformation was identified on MRI after the patient exhibited recurrent headaches beginning at age 5 years. Obstructive sleep apnea diagnosed via sleep study drastically improved with surgical correction. He was also diagnosed with severe anxiety and learning difficulties, that improved with intervention and demonstrated obsessive-compulsive disorder (OCD)-like behaviors, such as, frequent hand washing and a heightened concern for germs and cleanliness. The patient has an FOC of 52 cm, which is the 5th percentile for his age group but is otherwise non-dysmorphic and normal growth with height and weight at the 53rd and 36th percentiles respectively. The patient did not have congenital anomalies of the kidney and urinary tract or heart defects, a highly prevalent observed phenotype in prior reports of NECRC.

 

Diagnostic Workup
Initial genetic testing, including a chromosomal microarray and Fragile X testing, were negative. However, trio whole exome sequencing revealed a pathogenic variant in ZMYM2 as well as biallelic variants of uncertain significance (VUS) in the TUBGCP2 gene. The pathogenic variant in ZMYM2 was a de novo, single nucleotide deletion (c.1458del) causing a frameshift that introduced a premature stop codon 20 amino acids downstream (p.Ile486Metfs*20), leading to a truncated protein product.

Treatment and Management
The patient had a normal renal ultrasound prior to his diagnosis of NECRC. Following the NECRC diagnosis, the patient also had an echocardiogram and electrocardiogram to screen for congenital heart defects, both of which were normal.  As there is currently no cure or evidence-based protocols for NECRC the patient’s care is symptom-based and guided by prior presentations and physician judgment.

 

Outcome and Follow-Up
Due to increasing reports of seizures in genetic databases in individuals with NECRC, the family was educated on recognizing signs of seizures. Otherwise, the patient is to follow-up with the genetics team in two years or upon presentation of new symptoms or concerns.

 

Discussion
Consistent with prior reports on NECRC, this patient has relative microcephaly (5th percentile), learning difficulties, and sleep disturbances. However, unlike other individuals with pathogenic variants in this gene, the patient also has bilateral retinal colobomas, severe anxiety, symptoms resembling obsessive-compulsive disorder, and Arnold-Chiari Type 1 malformation, without any renal or cardiac findings.

 

Conclusion
This report describes an individual with a pathogenic variant in ZMYM2 associated with NECRC. Our patient presented with novel phenotypic features, expanding the phenotypic spectrum of NECRC and providing evidence of significant variable expressivity. Further research is needed to fully understand the molecular mechanisms and the phenotypic spectrum associated with NECRC.

 

Agenda

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