Limb-Girdle Muscular Dystrophy and Distal Myopathy

Gene: DNMT3B

I don't know

FSHD shares some features with LGMD.
Two families reported with FSHD2. In one family carriers of the heterozygous DNMT3B missense variant (c.1579T>C) had reduced DNA methylation levels at the D4Z4 repeat array and were more likely to develop FSHD in comparison to other family members carrying an identical permissive 4qA allele of 9 D4Z4 units. In the other family, digenic inheritance of a heterozygous DNMT3B missense variant (c.2072C>T) and a permissive 4qA allele of 13 D4Z4 units induced hypomethylation at the D4Z4 repeat array but only one of the two family members was diagnosed with FSHD. A mouse model with an in-frame deletion (similar to the reported missense variants) does not induce a skeletal muscle pathology nor does it increase the extremely low DUX4 transcript levels in skeletal muscles of a FSHD transgenic mouse. The mouse model also suggested that Smchd1 may have a more potent role in DUX4 derepression than Dnmt3b.
Sources: Literature

Created: 6 Jun 2022, 2:01 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Facioscapulohumeral muscular dystrophy MONDO:0001347

Publications

• 27153398
• 33004076

Green List (high evidence)

Well-established disease-gene association; more than 20 unrelated individuals; three mouse models Homozygous and compound heterozygous missense, nonsense, splice-site (leading to 3aa insertion) result in LOF disease mechanism. Individuals typically presented with immunodeficiencies (decreased immunoglobulin production, low T/B/NK cells), centric instability, facial anomalies and recurrent respiratory infections; however, severity varies.

Created: 27 Jul 2021, 6:39 a.m. | Last Modified: 27 Jul 2021, 6:39 a.m.

Panel Version: 0.8524

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Immunodeficiency-centromeric instability-facial anomalies syndrome 1 MIM# 242860; facial dysmorphic features; flat nasal bridge; developmental delay; macroglossia; bacterial/opportunistic infections (recurrent); malabsorption; cytopaenia; malignancies; multiradial configurations of chromosomes 1, 9, 16; Hypogammaglobulinaemia; agammaglobulinaemia; variable antibody deficiency; decreased immunoglobulin production; low T/B/NK cells

Publications

• 20587527
• 10555141
• 17359920
• 9718351
• 10647011
• 11102980
• 12239717