Low penetrance in facioscapulohumeral muscular dystrophy type 1 with large pathological D4Z4 alleles: a cross-sectional multicenter study.

Emmanuelle Salort‐Campana ,Françoise Bouhour,Guilhem Solé,Estelle Charles,Nicolas Levy,Marc Bartoli,Karine Nguyen,Christophe Vial,Claude Desnuelle,Sabrina Sacconi,Xavier Ferrer,Elisabeth Ollagnon,Shahram Attarian,Jean Pouget,C Tranchant ,Thierry Küntzer ,Julien Niederhäuser ,Marie-Christine Arné-Bès ,Frédérique Magdinier ,R Bernard ,Andoni Echaniz‐Laguna ,Aleksandra Nadaj‐Pakleza ,Élisabeth Jouve

doi:10.1186/s13023-014-0218-1

Abstract

BackgroundFacioscapulohumeral muscular dystrophy type 1(FSHD1) is an autosomal dominant disorder associated with the contraction of D4Z4 less than 11 repeat units (RUs) on chromosome 4q35. Penetrance in the range of the largest alleles is poorly known. Our objective was to study the penetrance of FSHD1 in patients carrying alleles ranging between 6 to10 RUs and to evaluate the influence of sex, age, and several environmental factors on clinical expression of the disease.MethodsA cross-sectional multicenter study was conducted in six French and one Swiss neuromuscular centers. 65 FSHD1 affected patients carrying a 4qA allele of 6–10 RUs were identified as index cases (IC) and their 119 at-risk relatives were included. The age of onset was recorded for IC only. Medical history, neurological examination and manual muscle testing were performed for each subject. Genetic testing determined the allele size (number of RUs) and the 4qA/4qB allelic variant. The clinical status of relatives was established blindly to their genetic testing results. The main outcome was the penetrance defined as the ratio between the number of clinically affected carriers and the total number of carriers.ResultsAmong the relatives, 59 carried the D4Z4 contraction. At the clinical level, 34 relatives carriers were clinically affected and 25 unaffected. Therefore, the calculated penetrance was 57% in the range of 6–10 RUs. Penetrance was estimated at 62% in the range of 6–8 RUs, and at 47% in the range of 9–10 RUs. Moreover, penetrance was lower in women than men. There was no effect of drugs, anesthesia, surgery or traumatisms on the penetrance.ConclusionsPenetrance of FSHD1 is low for largest alleles in the range of 9–10 RUs, and lower in women than men. This is of crucial importance for genetic counseling and clinical management of patients and families.

Highlights

Facioscapulohumeral muscular dystrophy type 1(FSHD1) is an autosomal dominant disorder associated with the contraction of D4Z4 less than 11 repeat units (RUs) on chromosome 4q35
Penetrance of FSHD type 1 (FSHD1) is low for largest alleles in the range of 9–10 RUs, and lower in women than men
This is of crucial importance for genetic counseling and clinical management of patients and families

Summary

Introduction

Facioscapulohumeral muscular dystrophy type 1(FSHD1) is an autosomal dominant disorder associated with the contraction of D4Z4 less than 11 repeat units (RUs) on chromosome 4q35. Our objective was to study the penetrance of FSHD1 in patients carrying alleles ranging between 6 to RUs and to evaluate the influence of sex, age, and several environmental factors on clinical expression of the disease. Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder with variable severity and inter- and intra-familial heterogeneity [1,2]. The unique association of FSHD1 with a specific haplotype remains controversial as some FSHD1 patients carry a D4Z4 contraction without the common 4A161PAS haplotype [7]. Few studies reported the phenotypic spectrum associated with the upper pathological alleles (9–10 RUs). A better knowledge of penetrance in this range is necessary for improving genetic counseling, in the context of predictive testing and prenatal diagnosis in FSHD families

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