Monosomy 18p is a risk factor for facioscapulohumeral dystrophy

Area of Science:

• Genetics and Molecular Biology
• Human Disease and Syndromes
• Epigenetics

Background:

• 18p deletion syndrome results from monosomy of chromosome 18's short arm, causing cognitive impairment and facial dysmorphism.
• The SMCHD1 gene, crucial for chromosome structure, is often hemizygous in 18p deletion patients.
• Facioscapulohumeral muscular dystrophy type 2 (FSHD2) arises from a combination of SMCHD1 mutations and specific D4Z4 repeats on chromosome 4.

Purpose of the Study:

• To investigate the risk of developing FSHD in individuals with 18p deletions.
• To analyze the molecular and epigenetic characteristics of the D4Z4 region in patients with 18p deletions.
• To assess clinical muscle features in 18p deletion patients with specific D4Z4 repeats.

Main Methods:

• Studied cellular systems from 18p deletion individuals for D4Z4 transcriptional and epigenetic profiles.
• Examined D4Z4 chromatin structure and DUX4 expression in SMCHD1-hemizygous fibroblasts.
• Conducted neurological examinations on 18p deletion patients from families with D4Z4 repeats.

Main Results:

• Fibroblasts from 18p deletion patients showed D4Z4 chromatin structures similar to FSHD2 and DUX4 expression post-transdifferentiation.
• Neurological assessments revealed muscle features consistent with FSHD in 18p deletion individuals with moderately sized D4Z4 repeats.
• The genetic combination of 18p deletion (leading to SMCHD1 haploinsufficiency) and specific D4Z4 alleles is associated with FSHD.

Conclusions:

• 18p deletions, particularly when combined with FSHD-permissive D4Z4 alleles, can lead to FSHD symptoms and molecular hallmarks.
• Recommends genetic characterization of D4Z4 repeat size and haplotype in 18p deletion patients.
• Suggests clinical monitoring for FSHD features in individuals with 18p deletions.