Novel TMEM63A mutation associated with transient hypomyelination of infancy - lessons from a previously negative whole-exome sequencing case: Three case reports

Abstract

BACKGROUND

Hypomyelinating leukodystrophies are rare neurodevelopmental disorders characterized by impaired myelin development and early motor delay. Hypomyelinating leukodystrophy type 19 (HLD-19), also termed transient hypomyelination of infancy, is caused by TMEM63A variants. It can clinically resemble other hypomyelinating leukodystrophies but is distinguished by developmental improvement. However, its phenotypic spectrum remains incompletely defined.

CASE SUMMARY

We describe 3 related individuals presenting in early infancy with nystagmus, hypotonia, and delayed motor milestones. Brain magnetic resonance imaging demonstrated diffuse hypomyelination, followed by progressive clinical improvement and normalization of myelination on serial imaging. Initial trio whole-exome sequencing was nondiagnostic. Reanalysis-prompted by recognition of additional affected relatives and refinement of human phenotype ontology (HPO) annotation-identified a novel heterozygous TMEM63A variant (c.146G>T; p.Gly49Val). The variant segregated with disease in multiple affected family members.

CONCLUSION

This familial series expands the clinical and genetic spectrum of TMEM63A-related HLD-19. It emphasizes that whole-exome sequencing reanalysis-particularly when family structure or phenotype evolves and when broader HPO terms are applied-can secure a diagnosis and improve counseling and prognostic guidance.

Keywords: Incomplete penetrance; Hypomyelinating leukodystrophy type 19; Hypomyelinating leukodystrophy; TMEM63A; Transient hypomyelination; Case report

Core Tip: Practice-changing diagnostic lesson: In children with early-onset nystagmus, hypotonia, and developmental delay-including hypomyelination syndrome-should be considered. When whole-exome sequencing is nondiagnostic, the appearance of new affected relatives or evolving new phenotype should trigger reanalysis using broader, iteratively refined human phenotype ontology terms, integrated with the suspected inheritance pattern. This strategy improves variant interpretation, increases diagnostic yield, and can ultimately end the diagnostic odyssey.