Do Not Trust the Pedigree: Reduced and Sex-Dependent Penetrance at a Novel Mutation Hotspot in ATL1 Blurs Autosomal Dominant Inheritance of Spastic Paraplegia

Rita Eva Varga, Rebecca Schüle, Hicham Fadel, Irene Valenzuela, Fiorella Speziani, Michael Gonzalez, Galina Rudenskaia, Gudrun Nürnberg, Holger Thiele, Janine Altmüller, Victoria Alvarez, Josep Gamez, James Y. Garbern, Peter Nürnberg, Stephan L Zuchner, Christian Beetz

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

The hereditary spastic paraplegias (HSPs), a group of neurodegenerative movement disorders, are among the genetically most heterogeneous clinical conditions. Still, the more than 50 forms known so far apparently explain less than 80% of cases. The present study identified two large HSP families, which seemed to show an autosomal recessive and an X-linked inheritance pattern. A set of genetic analyses including exome sequencing revealed plausible mutations only when assuming incomplete/sex-dependent penetrance of adjacent alterations in the autosomal dominant HSP gene ATL1 (c.1243C>T and c.1244G>A, respectively). By screening of additional HSP patients for the presence of these alterations, we identified three more cases and obtained additional evidence for reduced penetrance. Bisulfate sequencing and haplotype analysis indicated that c.1243C and c.1244G constitute a mutational hotspot. Our findings suggest that misinterpretation of inheritance patterns and, consequently, misselection of candidate genes to be screened in gene-focused approaches contribute to the apparently missing heritability in HSP and, potentially, in other genetically heterogeneous disorders. Inheritance patterns usually guide gene selection in mutational screening strategies. By whole exome sequencing of index cases with apparently novel forms of spastic paraplegia, we identify a mutational hotspot in the known dominant gene ATL1 and show that corresponding alterations are associated with a highly reduced and partially sex-dependent risk of developing the disease. Our findings suggest that misleading family history may contribute to missing heritability in genetically heterogeneous disorders.

Original languageEnglish
Pages (from-to)860-863
Number of pages4
JournalHuman Mutation
Volume34
Issue number6
DOIs
StatePublished - Jun 1 2013

Fingerprint

Hereditary Spastic Paraplegia
Penetrance
Pedigree
Inheritance Patterns
Mutation
Exome
Genes
Dominant Genes
X-Linked Genes
Paraplegia
Movement Disorders
Neurodegenerative Diseases
Haplotypes
Autosomal dominant Spastic paraplegia 10

Keywords

  • ATL1
  • Inheritance pattern
  • Pedigree
  • Penetrance
  • Spastic paraplegia

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Do Not Trust the Pedigree : Reduced and Sex-Dependent Penetrance at a Novel Mutation Hotspot in ATL1 Blurs Autosomal Dominant Inheritance of Spastic Paraplegia. / Varga, Rita Eva; Schüle, Rebecca; Fadel, Hicham; Valenzuela, Irene; Speziani, Fiorella; Gonzalez, Michael; Rudenskaia, Galina; Nürnberg, Gudrun; Thiele, Holger; Altmüller, Janine; Alvarez, Victoria; Gamez, Josep; Garbern, James Y.; Nürnberg, Peter; Zuchner, Stephan L; Beetz, Christian.

In: Human Mutation, Vol. 34, No. 6, 01.06.2013, p. 860-863.

Research output: Contribution to journalArticle

Varga, RE, Schüle, R, Fadel, H, Valenzuela, I, Speziani, F, Gonzalez, M, Rudenskaia, G, Nürnberg, G, Thiele, H, Altmüller, J, Alvarez, V, Gamez, J, Garbern, JY, Nürnberg, P, Zuchner, SL & Beetz, C 2013, 'Do Not Trust the Pedigree: Reduced and Sex-Dependent Penetrance at a Novel Mutation Hotspot in ATL1 Blurs Autosomal Dominant Inheritance of Spastic Paraplegia', Human Mutation, vol. 34, no. 6, pp. 860-863. https://doi.org/10.1002/humu.22309
Varga, Rita Eva ; Schüle, Rebecca ; Fadel, Hicham ; Valenzuela, Irene ; Speziani, Fiorella ; Gonzalez, Michael ; Rudenskaia, Galina ; Nürnberg, Gudrun ; Thiele, Holger ; Altmüller, Janine ; Alvarez, Victoria ; Gamez, Josep ; Garbern, James Y. ; Nürnberg, Peter ; Zuchner, Stephan L ; Beetz, Christian. / Do Not Trust the Pedigree : Reduced and Sex-Dependent Penetrance at a Novel Mutation Hotspot in ATL1 Blurs Autosomal Dominant Inheritance of Spastic Paraplegia. In: Human Mutation. 2013 ; Vol. 34, No. 6. pp. 860-863.
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abstract = "The hereditary spastic paraplegias (HSPs), a group of neurodegenerative movement disorders, are among the genetically most heterogeneous clinical conditions. Still, the more than 50 forms known so far apparently explain less than 80{\%} of cases. The present study identified two large HSP families, which seemed to show an autosomal recessive and an X-linked inheritance pattern. A set of genetic analyses including exome sequencing revealed plausible mutations only when assuming incomplete/sex-dependent penetrance of adjacent alterations in the autosomal dominant HSP gene ATL1 (c.1243C>T and c.1244G>A, respectively). By screening of additional HSP patients for the presence of these alterations, we identified three more cases and obtained additional evidence for reduced penetrance. Bisulfate sequencing and haplotype analysis indicated that c.1243C and c.1244G constitute a mutational hotspot. Our findings suggest that misinterpretation of inheritance patterns and, consequently, misselection of candidate genes to be screened in gene-focused approaches contribute to the apparently missing heritability in HSP and, potentially, in other genetically heterogeneous disorders. Inheritance patterns usually guide gene selection in mutational screening strategies. By whole exome sequencing of index cases with apparently novel forms of spastic paraplegia, we identify a mutational hotspot in the known dominant gene ATL1 and show that corresponding alterations are associated with a highly reduced and partially sex-dependent risk of developing the disease. Our findings suggest that misleading family history may contribute to missing heritability in genetically heterogeneous disorders.",
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AU - Schüle, Rebecca

AU - Fadel, Hicham

AU - Valenzuela, Irene

AU - Speziani, Fiorella

AU - Gonzalez, Michael

AU - Rudenskaia, Galina

AU - Nürnberg, Gudrun

AU - Thiele, Holger

AU - Altmüller, Janine

AU - Alvarez, Victoria

AU - Gamez, Josep

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AB - The hereditary spastic paraplegias (HSPs), a group of neurodegenerative movement disorders, are among the genetically most heterogeneous clinical conditions. Still, the more than 50 forms known so far apparently explain less than 80% of cases. The present study identified two large HSP families, which seemed to show an autosomal recessive and an X-linked inheritance pattern. A set of genetic analyses including exome sequencing revealed plausible mutations only when assuming incomplete/sex-dependent penetrance of adjacent alterations in the autosomal dominant HSP gene ATL1 (c.1243C>T and c.1244G>A, respectively). By screening of additional HSP patients for the presence of these alterations, we identified three more cases and obtained additional evidence for reduced penetrance. Bisulfate sequencing and haplotype analysis indicated that c.1243C and c.1244G constitute a mutational hotspot. Our findings suggest that misinterpretation of inheritance patterns and, consequently, misselection of candidate genes to be screened in gene-focused approaches contribute to the apparently missing heritability in HSP and, potentially, in other genetically heterogeneous disorders. Inheritance patterns usually guide gene selection in mutational screening strategies. By whole exome sequencing of index cases with apparently novel forms of spastic paraplegia, we identify a mutational hotspot in the known dominant gene ATL1 and show that corresponding alterations are associated with a highly reduced and partially sex-dependent risk of developing the disease. Our findings suggest that misleading family history may contribute to missing heritability in genetically heterogeneous disorders.

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