Early onset or syndromic epilepsy

Gene: TMEM106B

Comment on list classification: Rating Amber as only 2 individuals with seizures (both early-onset, before age 6 months) reported at present

Created: 12 Nov 2020, 3:02 p.m. | Last Modified: 12 Nov 2020, 3:02 p.m.

Panel Version: 2.206

New gene added by Konstantinos Varvagiannis. Associated with phenotype in OMIM, and is a 'probable' gene for 'TMEM106B related hypomyelinating leukodystrophy' in Gene2Phenotype.

Recurrent variant c.754G>A p.(Asp252Asn) identified in 6 unrelated families from different ethnicities. Clinical characteristics include hypomyelinating leukodystrophy (6/6), nystagmus (6/6), hypotonia (5/6), cognitive impairment (5/6), movement disorder (3/6) and seizures (2/6).

Created: 12 Nov 2020, 2:59 p.m. | Last Modified: 12 Nov 2020, 2:59 p.m.

Panel Version: 2.205

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Leukodystrophy, hypomyelinating, 16 OMIM:617964

Publications

• 29186371
• 29444210
• 30643851
• 32595021

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

I don't know

6 unrelated individuals with Leukodystrophy, hypomyelinating, 16 (MIM #617964) due to a recurrent TMEM106B variant have been reported to date in the literature (Simons et al 2017 - PMID: 29186371, Yan et al 2018 - PMID: 29444210, Ikemoto et al 2020 - PMID: 32595021).

While a 3 y.o. female described by Yan et al had DD (eg sitting at 9m, walking at 25m) with normal cognitive functioning, and a 38 y.o. female had borderline intellectual functioning (IQ 76), 4 affected individuals had ID. Among them, a 19 y.o. male with severe ID was also found to harbor a second de novo possibly damaging USP7 variant. Seizures have been reported in 2 unrelated subjects. [Clinical features are also summarized in table 1 - Ikemoto et al].

All harbored NM_001134232.2(TMEM106B):c.754G>A (p.Asp252Asn) which in almost all cases occurred as a de novo event. In a single case this variant was inherited from a mosaic parent with mild DD in infancy but normal cognition (reported by Simons et al).

As discussed by Ito et al (2018 - PMID: 30643851) the encoded protein is a structural component of the lysosomal membrane, playing a role on lysosome acidification. Acidity of the lysosome mediates multiple aspects of lysosomal function. Ito et al, using patient-derived fibroblasts assessed mRNA and protein levels. These were unaltered compared with controls. While TMEM106B had been previously shown to affect lysosome number, morphology and acidification, Ito et al demonstrated increased number of lysosomes in patient cells as well as impaired acidification compared to controls. As commented lysosomes are required for generation of myelin.

Recurrence of this missense variant, the presence of pLoF TMEM106B variants in gnomAD as well as the phenotypically normal Tmem106b null mice suggest that this variant may have a gain-of-function or dominant negative effect.

Genes for other forms of hypomyelinating lipodystrophy (incl. PLP1) have green rating in the ID panel.

Overall TMEM106B can be considered for the ID panel with green rating and the epilepsy panel with amber rating.
Sources: Literature

Created: 13 Jul 2020, 7:12 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Leukodystrophy, hypomyelinating, 16 (MIM #617964)

Publications

• 29186371
• 29444210
• 32595021

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments