title: Large scale genotype-phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy.
abstract: Facioscapulohumeral muscular dystrophy has been genetically linked to reduced numbers (≤ 8) of D4Z4 repeats at 4q35 combined with 4A(159/161/168) DUX4 polyadenylation signal haplotype. However, we have recently reported that 1.3% of healthy individuals carry this molecular signature and 19% of subjects affected by facioscapulohumeral muscular dystrophy do not carry alleles with eight or fewer D4Z4 repeats. Therefore, prognosis for subjects carrying or at risk of carrying D4Z4 reduced alleles has become more complicated. To test for additional prognostic factors, we measured the degree of motor impairment in a large group of patients affected by facioscapulohumeral muscular dystrophy and their relatives who are carrying D4Z4 reduced alleles. The clinical expression of motor impairment was assessed in 530 subjects, 163 probands and 367 relatives, from 176 unrelated families according to a standardized clinical score. The associations between clinical severity and size of D4Z4 allele, degree of kinship, gender, age and 4q haplotype were evaluated. Overall, 32.2% of relatives did not display any muscle functional impairment. This phenotype was influenced by the degree of relation with proband, because 47.1% of second- through fifth-degree relatives were unaffected, whereas only 27.5% of first-degree family members did not show motor impairment. The estimated risk of developing motor impairment by age 50 for relatives carrying a D4Z4 reduced allele with 1-3 repeats or 4-8 repeats was 88.7% and 55%, respectively. Male relatives had a mean score significantly higher than females (5.4 versus 4.0, P = 0.003). No 4q haplotype was exclusively associated with the presence of disease. In 13% of families in which D4Z4 alleles with 4-8 repeats segregate, the diagnosis of facioscapulohumeral muscular dystrophy was reported only in one generation. In conclusion, this large-scale analysis provides further information that should be taken into account when counselling families in which a reduced allele with 4-8 D4Z4 repeats segregates. In addition, the reduced expression of disease observed in distant relatives suggests that a family's genetic background plays a role in the occurrence of facioscapulohumeral muscular dystrophy. These results indicate that the identification of new susceptibility factors for this disease will require an accurate classification of families.
authors.affiliation: 1 Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, via Roma 67, 56126 Pisa, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Ricci
authors.forename: Isabella
authors.initials: I
authors.lastname: Scionti
authors.forename: Francesco
authors.initials: F
authors.lastname: Sera
authors.forename: Monica
authors.initials: M
authors.lastname: Govi
authors.forename: Roberto
authors.initials: R
authors.lastname: D'Amico
authors.forename: Ilaria
authors.initials: I
authors.lastname: Frambolli
authors.forename: Fabiano
authors.initials: F
authors.lastname: Mele
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Filosto
authors.forename: Liliana
authors.initials: L
authors.lastname: Vercelli
authors.forename: Lucia
authors.initials: L
authors.lastname: Ruggiero
authors.forename: Angela
authors.initials: A
authors.lastname: Berardinelli
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Antonini
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bucci
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Cao
authors.forename: Jessica
authors.initials: J
authors.lastname: Daolio
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Muzio
authors.forename: Rita
authors.initials: R
authors.lastname: Di Leo
authors.forename: Giuliana
authors.initials: G
authors.lastname: Galluzzi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Iannaccone
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Maggi
authors.forename: Valerio
authors.initials: V
authors.lastname: Maruotti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Moggio
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mongini
authors.forename: Lucia
authors.initials: L
authors.lastname: Morandi
authors.forename: Ana
authors.initials: A
authors.lastname: Nikolic
authors.forename: Ebe
authors.initials: E
authors.lastname: Pastorello
authors.forename: Enzo
authors.initials: E
authors.lastname: Ricci
authors.forename: Carmelo
authors.initials: C
authors.lastname: Rodolico
authors.forename: Lucio
authors.initials: L
authors.lastname: Santoro
authors.forename: Maura
authors.initials: M
authors.lastname: Servida
authors.forename: Gabriele
authors.initials: G
authors.lastname: Siciliano
authors.forename: Giuliano
authors.initials: G
authors.lastname: Tomelleri
authors.forename: Rossella
authors.initials: R
authors.lastname: Tupler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics* / Q000503:physiopathology; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D011379:Prognosis; D012042:Registries; D055815:Young Adult
chemical_list: C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins
keywords: D4Z4 reduced allele; disease expression; facioscapulohumeral muscular dystrophy; genotype–phenotype correlations; penetrance
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