Genetic Counseling and Testing for FSHD (Facioscapulohumeral Muscular Dystrophy) in the Israeli Population

Abstract

Facioscapulohumeral muscular dystrophy (FSHD), is a dominantly inherited, late onset, progressive disease. At present, no treatment or prevention of symptoms are available. There is considerable clinical variability, even within families. The gene whose defect causes FSHD has not been identified, but molecular diagnosis can be made by analyzing D4Z4 repeat length on chromosome 4q35. The results can support or rule out the clinical diagnosis of FSHD, but there are also "gray zone", non-conclusive results. During the years 2000-6, 66 individuals (including 7 asymptomatic individuals), were tested in our institute for D4Z4 repeat number. In 77% of the cases the results were conclusive: two thirds of them supported a diagnosis of FSHD while in a third this diagnosis was ruled out. In 23% the results were in the gray zone. Cognitive involvement was rare, occurring only when the D4Z4 repeat size was very small (<15 kb). Maximal utilization of the existing molecular test for FSHD demands detailed clinical and family pedigree information. We recommend that comprehensive genetic counseling always be given before and after molecular testing for FSHD, in addition to the neurological follow-up. Presymptomatic testing should only be offered when complete molecular evaluation can be offered, including 4qA and 4qB variant analysis.

Molecular combing compared to Southern blot for measuring D4Z4 contractions in FSHD

“…Current diagnostic testing for FSHD1 by SB may lead to indeterminate results in up to 23% of cases [30]. Technological limitations are evident when a deletion of the genomic sequence upstream of the chr 4 D4Z4 repeat units includes the p13E-11 probe region [31,32] and in cases with somatic mosaicism (i.e.…”

Multicolor Whole-Genome Mapping in Nanochannels for Genetic Analysis

“…FSHD is conventionally diagnosed using southern blotting tests but they only offer semi-quantitative results . In a small set of the specimen ( n = 87), southern blotting tests produced indeterminate results in 23% of the cases . As a result, alternative molecular combing, , optical mapping, and long-read sequencing-based approaches , for more efficient diagnosis of FSHD are gaining popularity.…”

“…33 In a small set of the specimen (n = 87), southern blotting tests produced indeterminate results in 23% of the cases. 34 As a result, alternative molecular combing, 35,36 optical mapping, 13 and long-read sequencing-based approaches 37,38 for more efficient diagnosis of FSHD are gaining popularity. Although long-read sequencing read lengths have improved significantly since their inception to date, whole-genome sequencing is expensive while targeted sequencing for long regions such as D4Z4 repeats remains infeasible.…”

Genetic Diagnosis of Facioscapulohumeral Muscular Dystrophy Type 1 Using Rare Variant Linkage Analysis and Long Read Genome Sequencing

“…Molecular diagnosis of FSHD1 is routinely made by Southern blotting, which requires a substantial amount of input DNA and often yields inconclusive results in up to 23% of cases 8 .…”