Hendrika B. Ginjaar

Leiden University Medical Center

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Jan J.G.M. Verschuuren

Leiden University Medical Center

J.C. van den Bergen

University Medical Center Utrecht

Volker Straub

Newcastle upon Tyne Hospitals NHS Foundation Trust

Egbert Bakker

Leiden University

Anneke Maat‐Kievit

Erasmus University Rotterdam

Alessandra Ferlini

University of Ferrara

Jan G. Post

University Medical Center Utrecht

Nicol C. Voermans

Radboud University Nijmegen

Hanns Lochmüller

Children's Hospital of Eastern Ontario

Monika Hiller

Leiden University Medical Center

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Leiden University Medical Center

Leiden University

Erasmus MC

University of Amsterdam

Radboud University Nijmegen

Radboud University Medical Center

Amsterdam University Medical Centers

Great Ormond Street Hospital

University College London

Inserm

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An urgent need for a change in policy revealed by a study on prenatal testing for Duchenne muscular dystrophy

European Journal of Human Genetics (2012)

Apollonia T.J.M. Helderman-van den Enden K. Madan Martijn H. Breuning Annemieke H. van der Hout Egbert Bakker

Prenatal diagnosis for Duchenne muscular dystrophy (DMD) was introduced in the Netherlands in 1984. We have investigated the impact of 26 years (1984–2009) of prenatal testing. Of the 635 prenatal diagnoses, 51% were males; nearly half (46%) of these were affected or had an increased risk of DMD. As a result 145 male fetuses were aborted and 174 unaffected boys were born. The vast majority (78%) of females, now 16 years or older, who were identified prenatally have not been tested for carrier status. Their average risk of being a carrier is 28%. We compared the incidences of DMD in the periods 1961–1974 and 1993–2002. The incidence of DMD did not decline but the percentage of first affected boys increased from 62 to 88%. We conclude that a high proportion of families with de novo mutations in the DMD gene cannot make use of prenatal diagnosis, partly because the older affected boys are not diagnosed before the age of five. Current policy, widely accepted in the genetic community, dictates that female fetuses are not tested for carrier status. These females remain untested as adults and risk having affected offspring as well as progressive cardiac disease. We see an urgent need for a change in policy to improve the chances of prevention of DMD. The first step would be to introduce neonatal screening of males. The next is to test females for carrier status if requested, prenatally if fetal DNA is available or postnatally even before adulthood.

Carrier testing

Advanced maternal age

10.1038/ejhg.2012.101

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Validation of genetic modifiers for Duchenne muscular dystrophy: a multicentre study assessingSPP1andLTBP4variants

Journal of Neurology Neurosurgery & Psychiatry (2014)

J.C. van den Bergen Monika Hiller Stefan Böhringer Linda Vijfhuizen Hendrika B. Ginjaar

Objective

Duchenne muscular dystrophy (DMD) is characterised by progressive muscle weakness. It has recently been reported that single nucleotide polymorphisms (SNPs) located in the SPP1 and LTBP4 loci can account for some of the inter-individual variability observed in the clinical disease course. The validation of genetic association in large independent cohorts is a key process for rare diseases in order to qualify prognostic biomarkers and stratify patients in clinical trials.

Methods

Duchenne patients from five European neuromuscular centres were included. Information about age at wheelchair dependence and steroid use was gathered. Melting curve analysis of PCR fragments or Sanger sequencing were used to genotype SNP rs28357094 in the SPP1 gene in 336 patients. The genotype of SNPs rs2303729, rs1131620, rs1051303 and rs10880 in the LTBP4 locus was determined in 265 patients by mass spectrometry. For both loci, a multivariate analysis was performed, using genotype/haplotype, steroid use and cohort as covariates.

Results

We show that corticosteroid treatment and the IAAM haplotype of the LTBP4 gene are significantly associated with prolonged ambulation in patients with DMD. There was no significant association between the SNP rs28357094 in the SPP1 gene and the age of ambulation loss.

Conclusions

This study underlines the importance of replicating genetic association studies for rare diseases in large independent cohorts to identify the most robust associations. We anticipate that genotyping of validated genetic associations will become important for the design and interpretation of clinical trials.

SNP

Linkage Disequilibrium

Genetic Association

10.1136/jnnp-2014-308409

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Citations (87)

Hypomorphic NOTCH3 Alleles Do Not Cause CADASIL in Humans

Human Mutation (2013)

Julie W. Rutten Elles M. J. Boon Michael Liem Johannes G. Dauwerse Margot J. Pont

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by stereotyped missense mutations in NOTCH3. Whether these mutations lead to the CADASIL phenotype via a neomorphic effect, or rather by a hypomorphic effect, is subject of debate. Here, we report two novel NOTCH3 mutations, both leading to a premature stop codon with predicted loss of NOTCH3 function. The first mutation, c.307C>T, p.Arg103*, was detected in two brothers aged 50 and 55 years, with a brain MRI and skin biopsy incompatible with CADASIL. The other mutation was found in a 40-year-old CADASIL patient compound heterozygous for a pathogenic NOTCH3 mutation (c.2129A>G, p.Tyr710Cys) and an intragenic frameshift deletion. The deletion was inherited from his father, who did not have the skin biopsy abnormalities seen in CADASIL patients. These individuals with rare NOTCH3 mutations indicate that hypomorphic NOTCH3 alleles do not cause CADASIL.

CADASIL

Skin biopsy

10.1002/humu.22432

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Diagnosis of becker muscular dystrophy: Results of Re-analysis of DNA samples

Muscle & Nerve (2015)

C.S.M. Straathof Dave van Heusden P.F. Ippel Jan G. Post Nicol C. Voermans

The phenotype of Becker muscular dystrophy (BMD) is highly variable, and the disease may be underdiagnosed. We searched for new mutations in the DMD gene in a cohort of previously undiagnosed patients who had been referred in the period 1985-1995.All requests for DNA analysis of the DMD gene in probands with suspected BMD were re-evaluated. If the phenotype was compatible with BMD, and no deletions or duplications were detected, DNA samples were screened for small mutations.In 79 of 185 referrals, no mutation was found. Analysis could be performed on 31 DNA samples. Seven different mutations, including 3 novel ones, were found. Long-term clinical follow-up is described.Refining DNA analysis in previously undiagnosed cases can identify mutations in the DMD gene and provide genetic diagnosis of BMD. A delayed diagnosis can still be valuable for the proband or the relatives of BMD patients.

Proband

Genetic Analysis

Mutation Testing

10.1002/mus.24691

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Citations (5)