Large genotype–phenotype study in carriers of D4Z4 borderline alleles provides guidance for facioscapulohumeral muscular dystrophy diagnosis
Abstract Facioscapulohumeral muscular dystrophy (FSHD) is a myopathy with prevalence of 1 in 20,000. Almost all patients affected by FSHD carry deletions of an integral number of tandem 3.3 kilobase repeats, termed D4Z4, located on chromosome 4q35. Assessment of size of D4Z4 alleles is commonly used...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2020
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/1f77ff0f42694a7eb9d9729bb0e05731 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:1f77ff0f42694a7eb9d9729bb0e05731 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:1f77ff0f42694a7eb9d9729bb0e057312021-12-02T16:18:04ZLarge genotype–phenotype study in carriers of D4Z4 borderline alleles provides guidance for facioscapulohumeral muscular dystrophy diagnosis10.1038/s41598-020-78578-72045-2322https://doaj.org/article/1f77ff0f42694a7eb9d9729bb0e057312020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78578-7https://doaj.org/toc/2045-2322Abstract Facioscapulohumeral muscular dystrophy (FSHD) is a myopathy with prevalence of 1 in 20,000. Almost all patients affected by FSHD carry deletions of an integral number of tandem 3.3 kilobase repeats, termed D4Z4, located on chromosome 4q35. Assessment of size of D4Z4 alleles is commonly used for FSHD diagnosis. However, the extended molecular testing has expanded the spectrum of clinical phenotypes. In particular, D4Z4 alleles with 9–10 repeat have been found in healthy individuals, in subjects with FSHD or affected by other myopathies. These findings weakened the strict relationship between observed phenotypes and their underlying genotypes, complicating the interpretation of molecular findings for diagnosis and genetic counseling. In light of the wide clinical variability detected in carriers of D4Z4 alleles with 9–10 repeats, we applied a standardized methodology, the Comprehensive Clinical Evaluation Form (CCEF), to describe and characterize the phenotype of 244 individuals carrying D4Z4 alleles with 9–10 repeats (134 index cases and 110 relatives). The study shows that 54.5% of index cases display a classical FSHD phenotype with typical facial and scapular muscle weakness, whereas 20.1% present incomplete phenotype with facial weakness or scapular girdle weakness, 6.7% display minor signs such as winged scapula or hyperCKemia, without functional motor impairment, and 18.7% of index cases show more complex phenotypes with atypical clinical features. Family studies revealed that 70.9% of relatives carrying 9–10 D4Z4 reduced alleles has no motor impairment, whereas a few relatives (10.0%) display a classical FSHD phenotype. Importantly all relatives of index cases with no FSHD phenotype were healthy carriers. These data establish the low penetrance of D4Z4 alleles with 9–10 repeats. We recommend the use of CCEF for the standardized clinical assessment integrated by family studies and further molecular investigation for appropriate diagnosis and genetic counseling. Especially in presence of atypical phenotypes and/or sporadic cases with all healthy relatives is not possible to perform conclusive diagnosis of FSHD, but all these cases need further studies for a proper diagnosis, to search novel causative genetic defects or investigate environmental factors or co-morbidities that may trigger the pathogenic process. These evidences are also fundamental for the stratification of patients eligible for clinical trials. Our work reinforces the value of large genotype–phenotype studies to define criteria for clinical practice and genetic counseling in rare diseases.Giulia RicciFabiano MeleMonica GoviLucia RuggieroFrancesco SeraLiliana VercelliCinzia BettioLucio SantoroTiziana MonginiLuisa VillaMaurizio MoggioMassimiliano FilostoMarina ScarlatoStefano C. PrevitaliSilvia Maria TripodiElena PegoraroRoberta TeleseAntonio Di MuzioCarmelo RodolicoElisabetta BucciGiovanni AntoniniMaria Grazia D’AngeloAngela BerardinelliLorenzo MaggiRachele PirasMaria Antonietta MaioliGabriele SicilianoGiuliano TomelleriCorrado AngeliniRossella TuplerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-12 (2020) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Giulia Ricci Fabiano Mele Monica Govi Lucia Ruggiero Francesco Sera Liliana Vercelli Cinzia Bettio Lucio Santoro Tiziana Mongini Luisa Villa Maurizio Moggio Massimiliano Filosto Marina Scarlato Stefano C. Previtali Silvia Maria Tripodi Elena Pegoraro Roberta Telese Antonio Di Muzio Carmelo Rodolico Elisabetta Bucci Giovanni Antonini Maria Grazia D’Angelo Angela Berardinelli Lorenzo Maggi Rachele Piras Maria Antonietta Maioli Gabriele Siciliano Giuliano Tomelleri Corrado Angelini Rossella Tupler Large genotype–phenotype study in carriers of D4Z4 borderline alleles provides guidance for facioscapulohumeral muscular dystrophy diagnosis |
| description |
Abstract Facioscapulohumeral muscular dystrophy (FSHD) is a myopathy with prevalence of 1 in 20,000. Almost all patients affected by FSHD carry deletions of an integral number of tandem 3.3 kilobase repeats, termed D4Z4, located on chromosome 4q35. Assessment of size of D4Z4 alleles is commonly used for FSHD diagnosis. However, the extended molecular testing has expanded the spectrum of clinical phenotypes. In particular, D4Z4 alleles with 9–10 repeat have been found in healthy individuals, in subjects with FSHD or affected by other myopathies. These findings weakened the strict relationship between observed phenotypes and their underlying genotypes, complicating the interpretation of molecular findings for diagnosis and genetic counseling. In light of the wide clinical variability detected in carriers of D4Z4 alleles with 9–10 repeats, we applied a standardized methodology, the Comprehensive Clinical Evaluation Form (CCEF), to describe and characterize the phenotype of 244 individuals carrying D4Z4 alleles with 9–10 repeats (134 index cases and 110 relatives). The study shows that 54.5% of index cases display a classical FSHD phenotype with typical facial and scapular muscle weakness, whereas 20.1% present incomplete phenotype with facial weakness or scapular girdle weakness, 6.7% display minor signs such as winged scapula or hyperCKemia, without functional motor impairment, and 18.7% of index cases show more complex phenotypes with atypical clinical features. Family studies revealed that 70.9% of relatives carrying 9–10 D4Z4 reduced alleles has no motor impairment, whereas a few relatives (10.0%) display a classical FSHD phenotype. Importantly all relatives of index cases with no FSHD phenotype were healthy carriers. These data establish the low penetrance of D4Z4 alleles with 9–10 repeats. We recommend the use of CCEF for the standardized clinical assessment integrated by family studies and further molecular investigation for appropriate diagnosis and genetic counseling. Especially in presence of atypical phenotypes and/or sporadic cases with all healthy relatives is not possible to perform conclusive diagnosis of FSHD, but all these cases need further studies for a proper diagnosis, to search novel causative genetic defects or investigate environmental factors or co-morbidities that may trigger the pathogenic process. These evidences are also fundamental for the stratification of patients eligible for clinical trials. Our work reinforces the value of large genotype–phenotype studies to define criteria for clinical practice and genetic counseling in rare diseases. |
| format |
article |
| author |
Giulia Ricci Fabiano Mele Monica Govi Lucia Ruggiero Francesco Sera Liliana Vercelli Cinzia Bettio Lucio Santoro Tiziana Mongini Luisa Villa Maurizio Moggio Massimiliano Filosto Marina Scarlato Stefano C. Previtali Silvia Maria Tripodi Elena Pegoraro Roberta Telese Antonio Di Muzio Carmelo Rodolico Elisabetta Bucci Giovanni Antonini Maria Grazia D’Angelo Angela Berardinelli Lorenzo Maggi Rachele Piras Maria Antonietta Maioli Gabriele Siciliano Giuliano Tomelleri Corrado Angelini Rossella Tupler |
| author_facet |
Giulia Ricci Fabiano Mele Monica Govi Lucia Ruggiero Francesco Sera Liliana Vercelli Cinzia Bettio Lucio Santoro Tiziana Mongini Luisa Villa Maurizio Moggio Massimiliano Filosto Marina Scarlato Stefano C. Previtali Silvia Maria Tripodi Elena Pegoraro Roberta Telese Antonio Di Muzio Carmelo Rodolico Elisabetta Bucci Giovanni Antonini Maria Grazia D’Angelo Angela Berardinelli Lorenzo Maggi Rachele Piras Maria Antonietta Maioli Gabriele Siciliano Giuliano Tomelleri Corrado Angelini Rossella Tupler |
| author_sort |
Giulia Ricci |
| title |
Large genotype–phenotype study in carriers of D4Z4 borderline alleles provides guidance for facioscapulohumeral muscular dystrophy diagnosis |
| title_short |
Large genotype–phenotype study in carriers of D4Z4 borderline alleles provides guidance for facioscapulohumeral muscular dystrophy diagnosis |
| title_full |
Large genotype–phenotype study in carriers of D4Z4 borderline alleles provides guidance for facioscapulohumeral muscular dystrophy diagnosis |
| title_fullStr |
Large genotype–phenotype study in carriers of D4Z4 borderline alleles provides guidance for facioscapulohumeral muscular dystrophy diagnosis |
| title_full_unstemmed |
Large genotype–phenotype study in carriers of D4Z4 borderline alleles provides guidance for facioscapulohumeral muscular dystrophy diagnosis |
| title_sort |
large genotype–phenotype study in carriers of d4z4 borderline alleles provides guidance for facioscapulohumeral muscular dystrophy diagnosis |
| publisher |
Nature Portfolio |
| publishDate |
2020 |
| url |
https://doaj.org/article/1f77ff0f42694a7eb9d9729bb0e05731 |
| work_keys_str_mv |
AT giuliaricci largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT fabianomele largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT monicagovi largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT luciaruggiero largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT francescosera largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT lilianavercelli largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT cinziabettio largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT luciosantoro largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT tizianamongini largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT luisavilla largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT mauriziomoggio largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT massimilianofilosto largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT marinascarlato largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT stefanocprevitali largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT silviamariatripodi largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT elenapegoraro largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT robertatelese largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT antoniodimuzio largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT carmelorodolico largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT elisabettabucci largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT giovanniantonini largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT mariagraziadangelo largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT angelaberardinelli largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT lorenzomaggi largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT rachelepiras largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT mariaantoniettamaioli largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT gabrielesiciliano largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT giulianotomelleri largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT corradoangelini largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis AT rossellatupler largegenotypephenotypestudyincarriersofd4z4borderlineallelesprovidesguidanceforfacioscapulohumeralmusculardystrophydiagnosis |
| _version_ |
1718384157800792064 |