Clinical spectrum of KIAA2022/NEXMIF pathogenic variants in males and females: Report of three patients from Indian kindred with a review of published patients.

BACKGROUND

In the last two decades, with the advent of whole-exome and whole-genome sequencing, supplemented with linkage analysis, more than 150 genes responsible for X-linked intellectual disability have been identified. Some genes like NEXMIF remain an enigmatic entity, as often the carrier females show wide phenotypic diversity ranging from completely asymptomatic to severe intellectual disability and drug-resistant epilepsy.

METHODS

We report three patients with pathogenic NEXMIF variants from an Indian family. All of them had language predominant developmental delay and later progressed to moderate intellectual disability with autistic features. We also reviewed the previously published reports of patients with pathogenic NEXMIF variants.

RESULTS

Together with the presented cases, 45 cases (24 symptomatic females) were identified from 15 relevant research items for analysis. Males have demonstrated a more severe intellectual disability and increasingly delayed walking age, autistic features, central hypotonia, and gastroesophageal reflux. In contrast, females have shown a predominant presentation with drug-resistant epilepsy and mild to moderate intellectual impairment. Notably, the affected females demonstrate a higher incidence of myoclonic, absence, and atonic seizures. The majority of the variants reported are nonsense or frameshift mutations, causing loss of function of the NEXMIF gene, while a considerable proportion possesses chromosomal translocations, microdeletions, and duplications.

CONCLUSIONS

NEXMIF gene mutations should be suspected in all cases of X-linked ID and autism cases in males or even in refractory epilepsy cases in females.