TMEM163

Inheritance Pattern: AD

Disease ID:MONDO:0859378

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0019046

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0859378

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0859378

Submitter: ClinGen

**TMEM163 Hypomyelinating Leukodystrophy 25, autosomal dominant** Preferred name: TMEM163-related hypomyelinating leukodystrophy TMEM163 was first reported in relation to autosomal dominant hypomyelinating leukodystrophy type 25 in 2022 (Yan et al., PMID: 35455965). Affected individuals present with nystagmus, visual deficits, global developmental delay, intellectual disability, hypotonia, ataxia, hypomyelination, and abnormalities of the corpus callosum. Onset occurs in infancy. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a consistent phenotype and no difference in molecular mechanisms or inheritance pattern; therefore, the single disease entity of hypomyelinating leukodystrophy type 25 has been maintained. The *TMEM163* gene encodes for transmembrane protein which is shown to be involved in zinc efflux (PMID: 31697912). Four missense variants have been reported in 6 probands across 2 publications (PMIDs: 35455965, 35953447) and are included in this curation. All variants occurred de novo in the affected individuals, except one case in which the variant was inherited from a mosaic parent. All variants had supporting functional data, yielding a total of 6 points of genetic evidence. The mechanism of pathogenicity has not been definitively determined although a dominant-negative mechanism has been suggested (PMID: 35455965, 35953447). This gene-disease relationship is also supported by experimental evidence (4.5 points). A zebrafish model demonstrated dysplasia of the larvae, locomotor disability as well as myelination defects as a result of reduced number of oligodendrocytes, recapitulating the human phenotype (PMID: 35455965). Rescue studies show that tmem163 knockdown zebrafish embryos injected with an in vitro synthesized mRNA encoding the human wild-type TMEM163 result in partial rescue, with 50% of embryos having no phenotype while embryos injected with mRNA harboring human TMEM163 variants resulted in embryos with a more severe phenotype (PMID: 35455965). A mouse oligodendrocyte cell line (‘oli-neu’) expressing the TMEM163 p.L76P mutant construct demonstrated significant reduction in cellular processes compared to wild type (PMID: 35953447). Given that these processes’ native role is to wrap around axons, thereby forming the myelin sheath, reduction of these processes is considered a cellular recapitulation of a hypomyelination phenotype. In summary, there is moderate evidence supporting the relationship between *TMEM163* and autosomal dominant hypomyelinating leukodystrophy 25, also known as TMEM163-related hypomyelinating leukodystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date April 15, 2026 (SOP Version 12).

Inheritance Pattern: AD

Disease ID:MONDO:0859378

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0859378

Submitter: Ambry Genetics