Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study

Guja Astrea†Email author,
Alessandro Romano†,
Corrado Angelini,
Carlo Giuseppe Antozzi,
Rita Barresi,
Roberta Battini,
Carla Battisti,
Enrico Bertini,
Claudio Bruno,
Denise Cassandrini,
Marina Fanin,
Fabiana Fattori,
Chiara Fiorillo,
Renzo Guerrini,
Lorenzo Maggi,
Eugenio Mercuri,
Federica Morani,
Marina Mora,
Francesca Moro,
Ilaria Pezzini,
Esther Picillo,
Michele Pinelli,
Luisa Politano,
Anna Rubegni,
Walter Sanseverino,
Marco Savarese,
Pasquale Striano,
Annalaura Torella,
Carlo Pietro Trevisan,
Rosanna Trovato,
Irina Zaraieva,
Francesco Muntoni,
Vincenzo Nigro,
Adele D’Amico,
Filippo M. SantorelliEmail author and
the Italian CMD Network

†Contributed equally

Orphanet Journal of Rare Diseases201813:170

https://doi.org/10.1186/s13023-018-0863-x

Received: 8 March 2018
Accepted: 29 June 2018
Published: 26 September 2018

Abstract

Background

Dystroglycanopathy (α-DG) is a relatively common, clinically and genetically heterogeneous category of congenital forms of muscular dystrophy (CMD) and limb-girdle muscular dystrophy (LGMD) associated with hypoglycosylated α-dystroglycan. To date, mutations in at least 19 genes have been associated with α-DG. One of them, GMPPB, encoding the guanosine-diphosphate-mannose (GDP-mannose) pyrophosphorylase B protein, has recently been associated with a wide clinical spectrum ranging from severe Walker-Warburg syndrome to pseudo-metabolic myopathy and even congenital myasthenic syndromes.

We re-sequenced the full set of known disease genes in 73 Italian patients with evidence of either reduced or nearly absent α-dystroglycan to assess genotype-phenotype correlations in this cohort. We used innovative bioinformatic tools to calculate the effects of all described GMPPB mutations on protein function and attempted to correlate them with phenotypic expressions.

Results

We identified 13 additional cases from 12 families and defined seven novel mutations. Patients displayed variable phenotypes including less typical pictures, ranging from asymptomatic hyperCKemia, to arthrogryposis and congenital clubfoot at birth, and also showed neurodevelopmental comorbidities, such as seizures and ataxic gait, as well as autism-spectrum disorder, which is seldom described in clinical reports of dystroglycanopathies. We also demonstrated that few mutations recur in the Italian GMPPB-mutated population and that alterations of protein stability are the main effects of GMPPB missense variants.

Conclusion

This work adds to the data on genotype-phenotype correlations in α-DG and offers new bionformatic tools to provide the conceptual framework needed to understand the complexity of these disorders.