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

Orphanet Journal of Rare Diseases

Shahram Attarian⁵  Jean Pouget⁶  Nicolas Levy^1,12  Thierry Kuntzer⁷  Xavier Ferrer²  Marie-Christine Arne-Bes³  Marc Bartoli⁶  Frederique Magdinier⁶  Christophe Vial⁹  Christine Tranchant⁴  Claude Desnuelle¹  Andoni Echaniz-Laguna⁴  Sabrina Sacconi¹  Françoise Bouhour⁹  Elisabeth Ollagnon⁸  Estelle Charles^1,10  Julien Niederhauser⁷  Aleksandra Nadaj-Pakleza^1,11  Guilhem Solé²  Elisabeth Jouve^1,10  Rafaelle Bernard^1,12  Karine Nguyen^1,12  Emmanuelle Salort-Campana^1,12 

[1]Neuromuscular Disease Specialized Center, Nice University Hospital, Nice, France

[2]Reference Center of Neuromuscular Disorders, CHU of Bordeaux, Pessac, France

[3]Reference Center of Neuromuscular Disorders, CHU of Toulouse, Toulouse, France

[4]Reference Center of Neuromuscular Disorders, Neurology Department, Hautepierre Hospital, Strasbourg, France

[5]AP-HM, Reference Center of Neuromuscular Disorders and ALS, Timone University Hospital, Aix-Marseille University, 264 rue Saint-Pierre, Marseille 13385, Cedex 05, France

[6]Aix Marseille Université - Inserm UMR_S 910 Medical Genetics and Functional Genomics, Marseille, France

[7]Nerve-Muscle Unit, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV), Lausanne, Switzerland

[8]Croix-Rousse Hospital, Lyon, France

[9]Electroneuromyography and Neuromuscular Department, GHE Neurologic hospital, Lyon 69677, Bron Cedex, France

[10]CIC-UPCET, Timone University Hospital, AP-HM, UMR CNRS Aix-Marseille University 6193, Marseille, France

[11]Centre de Référence des Maladies Neuromusculaires Nantes-Angers, Service de Neurologie, CHU d’Angers, Angers, France

[12]AP-HM, Department of Medical Genetics, Timone University Hospital, Marseille, France

关键词: D4Z4;    FSHD1;    Penetrance;    Facioscapulohumeral muscular dystrophy;   

Others  :  1138527
DOI  :  10.1186/s13023-014-0218-1

 received in 2014-10-14, accepted in 2014-12-29,  发布年份 2015

【 摘 要 】

Background

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 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.

Methods

A 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.

Results

Among 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.

Conclusions

Penetrance 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.

【 授权许可】

   
2015 Salort-Campana et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Mostacciuolo ML, Pastorello E, Vazza G, Miorin M, Angelini C, Tomelleri G, et al.: Facioscapulohumeral muscular dystrophy: epidemiological and molecular study in a north-east Italian population sample. Clin Genet 2009, 75:550-5.
• [2]Padberg GW: Facioscapulohumeral Disease. University of Leiden, Leiden, The Netherlands; 1982.
• [3]van Deutekom JC, Wijmenga C, van Tienhoven EA, Gruter AM, Hewitt JE, Padberg GW, et al.: FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit. Hum Mol Genet 1993, 2:2037-42.
• [4]Lemmers RJ, de Kievit P, Sandkuijl L, Padberg GW, van Ommen GJ, Frants RR, et al.: Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere. Nat Genet 2002, 32:235-6.
• [5]Lemmers RJ, Wohlgemuth M, Frants RR, Padberg GW, Morava E, van der Maarel SM: Contractions of D4Z4 on 4qB subtelomeres do not cause facioscapulohumeral muscular dystrophy. Am J Hum Genet 2004, 75:1124-30.
• [6]Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camaño P, Dauwerse JG, et al.: A unifying genetic model for facioscapulohumeral muscular dystrophy. Science 2010, 329:1650-3.
• [7]Scionti I, Greco F, Ricci G, Govi M, Arashiro P, Vercelli L, et al.: Large-scale population analysis challenges the current criteria for the molecular diagnosis of fascioscapulohumeral muscular dystrophy. Am J Hum Genet 2012, 90:628-35.
• [8]Ricci G, Scionti I, Sera F, Govi M, D'Amico R, Frambolli I, et al.: Large scale genotype-phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy. Brain 2013, 136:3408-17.
• [9]Sakellariou P, Kekou K, Fryssira H, Sofocleous C, Manta P, Panousopoulou A, et al.: Mutation spectrum and phenotypic manifestation in FSHD Greek patients. Neuromuscul Disord 2012, 22:339-49.
• [10]Butz M, Koch MC, Muller-Felber W, Lemmers RJ, van der Maarel SM, Schreiber H: Facioscapulohumeral muscular dystrophy. Phenotype-genotype correlation in patients with borderline D4Z4 repeat numbers. J Neurol 2003, 250:932-7.
• [11]Vielhaber S, Jakubiczka S, Schroder JM, Sailer M, Feistner H, Heinze HJ, et al.: Facioscapulohumeral muscular dystrophy with EcoRI/BlnI fragment size of more than 32 kb. Muscle Nerve 2002, 25:540-8.
• [12]Felice KJ, Whitaker CH: The clinical features of facioscapulohumeral muscular dystrophy associated with borderline (>/=35 kb) 4q35 EcoRI fragments. J Clin Neuromuscul Dis 2005, 6:119-26.
• [13]Galluzzi G, Deidda G, Cacurri S, Colantoni L, Piazzo N, Vigneti E, et al.: Molecular analysis of 4q35 rearrangements in fascioscapulohumeral muscular dystrophy (FSHD): application to family studies for a correct genetic advice and a reliable prenatal diagnosis of the disease. Neuromuscul Disord 1999, 9:190-8.
• [14]Ricci E, Galluzzi G, Deidda G, Cacurri S, Colantoni L, Merico B, et al.: Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q35 locus and clinical phenotype. Ann Neurol 1999, 45:751-7.
• [15]Padberg GW, Lunt PW, Koch M, Fardeau M: Diagnostic criteria for facioscapulohumeral muscular dystrophy. Neuromuscul Disord 1991, 1:231-4.
• [16]Scionti I, Fabbri G, Fiorillo C, Ricci G, Greco F, D'Amico R, et al.: Facioscapulohumeral muscular dystrophy: new insights from compound heterozygotes and implication for prenatal genetic counselling. J Med Genet 2012, 49:171-8.
• [17]Lunt PW, Compston DA, Harper PS: Estimation of age dependent penetrance in facioscapulohumeral muscular dystrophy by minimising ascertainment bias. J Med Genet 1989, 26:755-60.
• [18]Tonini MM, Passos-Bueno MR, Cerqueira A, Matioli SR, Pavanello R, Zatz M: Asymptomatic carriers and gender differences in facioscapulohumeral muscular dystrophy (FSHD). Neuromuscul Disord 2004, 14:33-8.
• [19]Zatz M, Marie S, Cerqueira A, Vainzof M, Pavanello R, Passos BM: The facioscapulohumeral muscular dystrophy (FSHD1) gene affects males more severely and more frequently than females. Am J Med Genet 1998, 77:155-61.
• [20]Goto K, Nishino I, Hayashi YK: Very low penetrance in 85 Japanese families with facioscapulohumeral muscular dystrophy 1A. J Med Genet 2004, 41:e12.
• [21]Busse K, Kohler J, Stegmann K, Pongratz D, Koch MC, Schreiber H: An inherited 4q35-EcoRI-DNA-fragment of 35 kb in a family with a sporadic case of facioscapulohumeral muscular dystrophy (FSHD). Neuromuscul Disord 2000, 10:178-81.
• [22]Vitelli F, Villanova M, Malandrini A, Bruttini M, Piccini M, Merlini L, et al.: Inheritance of a 38-kb fragment in apparently sporadic facioscapulohumeral muscular dystrophy. Muscle Nerve 1999, 22:1437-41.
• [23]Padberg GW, Frants RR, Brouwer OF, Wijmenga C, Bakker E, Sandkuijl LA: Facioscapulohumeral muscular dystrophy in the Dutch population. Muscle Nerve 1995, 2(Suppl):81-4.
• [24]Pastorello E, Cao M, Trevisan CP: Atypical onset in a series of 122 cases with FacioScapuloHumeral Muscular Dystrophy. Clin Neurol Neurosurg 2012, 114:230-4.
• [25]The FSH-DY group: A prospective, quantitative study of the natural history of facioscapulohumeral muscular dystrophy (FSHD): implications for therapeutic trials Neurology 1997, 48:38-46.
• [26]Lunt PW, Jardine PE, Koch MC, Maynard J, Osborn M, Williams M, et al.: Correlation between fragment size at D4F104S1 and age at onset or at wheelchair use, with a possible generational effect, accounts for much phenotypic variation in 4q35-facioscapulohumeral muscular dystrophy (FSHD). Hum Mol Genet 1995, 4:951-8.
• [27]Lunt PW, Harper PS: Genetic counselling in facioscapulohumeral muscular dystrophy. J Med Genet 1991, 28:655-64.
• [28]Statland JM, Tawil R: Risk of functional impairment in Facioscapulohumeral muscular dystrophy. Muscle Nerve 2014, 49:520-7.
• [29]Klinge L, Eagle M, Haggerty ID, Roberts CE, Straub V, Bushby KM: Severe phenotype in infantile facioscapulohumeral muscular dystrophy. Neuromuscul Disord 2006, 16:553-8.
• [30]Trevisan CP, Pastorello E, Tomelleri G, Vercelli L, Bruno C, Scapolan S, et al.: Facioscapulohumeral muscular dystrophy: hearing loss and other atypical features of patients with large 4q35 deletions. Eur J Neurol 2008, 15:1353-8.
• [31]van der Maarel SM, Tawil R, Tapscott SJ: Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. Trends Mol Med 2011, 17:252-8.
• [32]Lemmers RJ, Tawil R, Petek LM, Balog J, Block GJ, Santen GW, et al.: Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet 2012, 44:1370-4.
• [33]Sacconi S, Lemmers RJ, Balog J, van der Vliet PJ, Lahaut P, van Nieuwenhuizen MP, et al.: The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. Am J Hum Genet 2013, 93:744-51.