Neuropediatrics 2020; 51(01): 072-075
DOI: 10.1055/s-0039-1695787
Short Communication
Georg Thieme Verlag KG Stuttgart · New York

Just Expect It: Compound Heterozygous Variants of POMT1 in a Consanguineous Family—The Role of Next Generation Sequencing in Neuromuscular Disorders

Maja von der Hagen
1   Abteilung Neuropädiatrie, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
Lena-Luise Becker
2   Charité–Universitätsmedizin Berlin, Klinik für Pädiatrie mit Schwerpunkt Neurologie, Augustenburger Platz 1, Berlin, Germany
3   Charité—Universitätsmedizin Berlin, Sozialpädiatrisches Zentrum, Augustenburger Platz 1, Berlin, Germany
4   Charité—Universitätsmedizin Berlin, Institut für Zell- und Neurobiologie, Charité Platz 1, Berlin, Germany
,
Thomas F. Wienker
5   Max-Planck Institute for Molecular Genetics, Ihnestraße 63-73, Berlin, Germany
,
Martin Smitka
1   Abteilung Neuropädiatrie, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
Luciana Musante
5   Max-Planck Institute for Molecular Genetics, Ihnestraße 63-73, Berlin, Germany
,
Hans-Hilger Ropers
5   Max-Planck Institute for Molecular Genetics, Ihnestraße 63-73, Berlin, Germany
,
Angela Huebner
6   Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
Hao Hu*
5   Max-Planck Institute for Molecular Genetics, Ihnestraße 63-73, Berlin, Germany
7   Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou, China
,
Angela M. Kaindl*
2   Charité–Universitätsmedizin Berlin, Klinik für Pädiatrie mit Schwerpunkt Neurologie, Augustenburger Platz 1, Berlin, Germany
3   Charité—Universitätsmedizin Berlin, Sozialpädiatrisches Zentrum, Augustenburger Platz 1, Berlin, Germany
4   Charité—Universitätsmedizin Berlin, Institut für Zell- und Neurobiologie, Charité Platz 1, Berlin, Germany
› Author Affiliations
Acknowledgments The authors thank the family members who participated in this study. This work was supported by the Max Planck Society and by the European Commission Framework Program 7 (FP7) project GENCODYS with grant number 241995, the German Research Foundation (SFB665, SFB1315), the Berlin Institute of Health (BIH), the Charité, and the Förderverein für chronisch kranke Kinder am Sozialpädiatrischen Zentrum (SPZ) der Charité e.V.. The German Muscular Dystrophy Network (MD-NET 01GM0302) was funded by the German Ministry of Education and Research (BMBF, Bonn, Germany).
Further Information

Publication History

13 March 2019

24 July 2019

Publication Date:
18 October 2019 (online)

Abstract

Muscular dystrophy-dystroglycanopathies (MDDG) are a group of genetically heterogeneous autosomal recessive disorders characterized by hypoglycosylation of α-dystroglycan. Here, we report on two female patients from a consanguineous Lebanese family that presented in early infancy with generalized muscle hypotonia and primary microcephaly. Brain magnetic resonance imaging (MRI) showed different degrees of hypoplasia of the cerebellar vermis and hypoplasia of corpus callosum. Muscle biopsy analyses revealed a muscular dystrophy with reduced expression of α-dystroglycan and merosin in immunoblot analyses. Homozygosity mapping failed to elucidate the causal mutation due to the accepted notion that, in consanguineous families, homozygote mutations cause disease. However, by applying whole exome sequencing, we identified a novel compound heterozygous POMT1 mutation that segregates with the phenotype and is in line with the clinical presentation. This underscores that a less expected compound heterozygous instead of homozygous mutation in a consanguineous marriage results in a recessive disorder and highlights the growing role of next generation sequencing in neuromuscular disorder diagnostics.

* Equal contribution.


Supplementary Material

 
  • References

  • 1 Toda T, Chiyonobu T, Xiong H. , et al. Fukutin and alpha-dystroglycanopathies. Acta Myol 2005; 24 (02) 60-63
  • 2 Taniguchi-Ikeda M, Morioka I, Iijima K, Toda T. Mechanistic aspects of the formation of α-dystroglycan and therapeutic research for the treatment of α-dystroglycanopathy: a review. Mol Aspects Med 2016; 51: 115-124
  • 3 Mercuri E, Messina S, Bruno C. , et al. Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study. Neurology 2009; 72 (21) 1802-1809
  • 4 Godfrey C, Clement E, Mein R. , et al. Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain 2007; 130 (Pt 10): 2725-2735
  • 5 Longman C, Brockington M, Torelli S. , et al. Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan. Hum Mol Genet 2003; 12 (21) 2853-2861
  • 6 Manya H, Chiba A, Yoshida A. , et al. Demonstration of mammalian protein O-mannosyltransferase activity: coexpression of POMT1 and POMT2 required for enzymatic activity. Proc Natl Acad Sci U S A 2004; 101 (02) 500-505
  • 7 Kim DS, Hayashi YK, Matsumoto H. , et al. POMT1 mutation results in defective glycosylation and loss of laminin-binding activity in alpha-DG. Neurology 2004; 62 (06) 1009-1011
  • 8 Bello L, Melacini P, Pezzani R. , et al. Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy. Eur J Hum Genet 2012; 20 (12) 1234-1239
  • 9 van Reeuwijk J, Maugenre S, van den Elzen C. , et al. The expanding phenotype of POMT1 mutations: from Walker-Warburg syndrome to congenital muscular dystrophy, microcephaly, and mental retardation. Hum Mutat 2006; 27 (05) 453-459
  • 10 von der Hagen M, Schallner J, Kaindl AM. , et al. Facing the genetic heterogeneity in neuromuscular disorders: linkage analysis as an economic diagnostic approach towards the molecular diagnosis. Neuromuscul Disord 2006; 16 (01) 4-13
  • 11 Hu H, Wienker TF, Musante L. , et al. Integrated sequence analysis pipeline provides one-stop solution for identifying disease-causing mutations. Hum Mutat 2014; 35 (12) 1427-1435
  • 12 Beltrán-Valero de Bernabé D, Currier S, Steinbrecher A. , et al. Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet 2002; 71 (05) 1033-1043
  • 13 Jiang YH, Yuen RK, Jin X. , et al. Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Am J Hum Genet 2013; 93 (02) 249-263
  • 14 Overall AD. The effect of population stratification on the frequency of compound heterozygosity. Genetica 2011; 139 (03) 403-409
  • 15 Li Y, Vinckenbosch N, Tian G. , et al. Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants. Nat Genet 2010; 42 (11) 969-972