Inheritance patterns in HSP easy to misinterpret

Posted - February 2014 in Research Highlights

Implications for choice of genetic tests and screens

 

A common finding in three research studies may be part of the reason that 20% or more of HSP cases can’t yet be explained by genetic identification.

 

Three scientific papers all support the finding that family inheritance patterns can be misleading in drawing conclusions about the type and spectrum of genetic mutations likely to be responsible for the HSP found in those families.

In one paper, what appears to be autosomal dominant inheritance turns out to be autosomal recessive inheritance… and in another paper, what appears to be autosomal recessive or sex-linked inheritance may well be autosomal dominant HSP. Both these studies were on mutations in Atlastin, which is associated with SPG3A HSP. In the third paper, one gene mutation in REEP2 is found responsible for both dominant and recessive inheritance in SPG72 HSP.

 

Paper 1: Do not trust the pedigree

 

Christian Beetz

Christian Beetz

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).

Stephan Züchner

Stephan Züchner

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.

*Editor’s note: Reduced penetrance is a phenomenon where a fully inherited genetic trait, such as a disease or disorder, fails to exhibit the expected phenotype. HSP is considered to have reduced penetrance, as a significant percentage of people with known HSP mutations do not ever exhibit a clinical-level of symptoms.

 

SOURCE:  Hum Mutat. 2013 Jun;34(6):860-3.  doi: 10.1002/humu.22309. Epub 2013 Apr 5.  © 2013 Wiley Periodicals, Inc.  PMID: 23483706 [PubMed – indexed for MEDLINE]

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 RE1, 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 S, Beetz C.

1Department of Clinical Chemistry, Jena University Hospital, Jena, Germany.

 

Paper 2: SPG3A example of caution needed in genetic screening

 

Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of disorders characterized by progressive spasticity and weakness of the lower limbs. Autosomal dominant and ‘pure’ forms of HSP account for ∼80% of cases in Western societies of whom 10% carry atlastin-1 (ATL1) gene mutations.

We report on a large consanguineous family segregating six members with early onset HSP. The pedigree was compatible with both autosomal dominant and autosomal recessive inheritance.

Whole-exome sequencing and segregation analysis revealed a homozygous novel missense variant c.353G>A, p.(Arg118Gln) in ATL1 in all six affected family members. Seven heterozygous carriers, five females and two males, showed no clinical signs of HSP with the exception of sub-clinically reduced vibration sensation in one adult female.

Our combined findings show that homozygosity for the ATL1 missense variant remains the only plausible cause of HSP, whereas heterozygous carriers are asymptomatic. This apparent autosomal recessive inheritance adds to the clinical complexity of spastic paraplegia 3A and calls for caution using directed genetic screening in HSP.

 

SOURCE:  Eur J Hum Genet. 2014 Jan 29. doi: 10.1038/ejhg.2014.5. [Epub ahead of print]  PMID: 24473461 (PubMed – as supplied by publisher) 

Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation.

Khan TN1, Klar J2, Tariq M1, Anjum Baig S3, Malik NA1, Yousaf R4, Baig SM1, Dahl N2.

Author information

1Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.

2Department of Immunology, Genetics and Pathology, Science for Life Laboratory at Uppsala University, Biomedical Center, Uppsala, Sweden.

3Department of Pathology, Children’s Hospital, Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan.

4Department of Neurology, Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan.

 

 

Paper 3: Both dominant and recessive inheritance found in mutations in the same gene

 

Giovanni Stevanin

Giovanni Stevanin

Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurological conditions. Their main pathogenic mechanisms are thought to involve alterations in endomembrane trafficking, mitochondrial function, and lipid metabolism.

With a combination of whole-genome mapping and exome sequencing, we identified three mutations in REEP2 in two families with HSP: a missense variant (c.107T>A [p.Val36Glu]) that segregated in the heterozygous state in a family with autosomal-dominant inheritance and a missense change (c.215T>A [p.Phe72Tyr]) that segregated in trans with a splice site mutation (c.105+3G>T) in a family with autosomal-recessive transmission.

REEP2 belongs to a family of proteins that shape the endoplasmic reticulum, an organelle that was altered in fibroblasts from an affected subject. In vitro, the p.Val36Glu variant in the autosomal-dominant family had a dominant-negative effect; it inhibited the normal binding of wild-type REEP2 to membranes. The missense substitution p.Phe72Tyr, in the recessive family, decreased the affinity of the mutant protein for membranes that, together with the splice site mutation, is expected to cause complete loss of REEP2 function.

Our findings illustrate how dominant and recessive inheritance can be explained by the effects and nature of mutations in the same gene. They have also important implications for genetic diagnosis and counseling in clinical practice because of the association of various modes of inheritance to this new clinico-genetic entity.

 

SOURCE:  Am J Hum Genet. 2014 Feb 6;94(2):268-77. doi: 10.1016/j.ajhg.2013.12.005. Epub 2014 Jan 2.  Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.  PMID: 24388663 [PubMed – in process]

Loss of Association of REEP2 with Membranes Leads to Hereditary Spastic Paraplegia.

Esteves T1, Durr A2, Mundwiller E3, Loureiro JL4, Boutry M5, Gonzalez MA6, Gauthier J7, El-Hachimi KH1, Depienne C2, Muriel MP5, Acosta Lebrigio RF6, Gaussen M1, Noreau A7, Speziani F6, Dionne-Laporte A7, Deleuze JF8, Dion P7, Coutinho P4, Rouleau GA7, Zuchner S6, Brice A9, Stevanin G10, Darios F11.

Author information:

1Université Pierre and Marie Curie – Paris VI, Unité Mixte de Recherche S975, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité 975, 75013 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7225, 75013 Paris, France; Laboratoire de Neurogénétique, Ecole Pratique des Hautes Etudes, Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.

2Université Pierre and Marie Curie – Paris VI, Unité Mixte de Recherche S975, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité 975, 75013 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7225, 75013 Paris, France; APHP, Centre de Génétique Moléculaire et Chromosomique, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.

3Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.

4UnIGENe and Centro de Genetica Preditiva e Preventiva, Institute for Molecular and Cellular Biology, 4050 Porto, Portugal.

5Université Pierre and Marie Curie – Paris VI, Unité Mixte de Recherche S975, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité 975, 75013 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7225, 75013 Paris, France.

6Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.

7Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada.

8Centre National de Genotypage, 91057 Evry, France.

9Université Pierre and Marie Curie – Paris VI, Unité Mixte de Recherche S975, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité 975, 75013 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7225, 75013 Paris, France; APHP, Centre de Génétique Moléculaire et Chromosomique, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.

10Université Pierre and Marie Curie – Paris VI, Unité Mixte de Recherche S975, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité 975, 75013 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7225, 75013 Paris, France; Laboratoire de Neurogénétique, Ecole Pratique des Hautes Etudes, Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France. Electronic address: [email protected]

11Université Pierre and Marie Curie – Paris VI, Unité Mixte de Recherche S975, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité 975, 75013 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7225, 75013 Paris, France. Electronic address: [email protected]

 

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