Proven germline mosaicism in a father of two children with CHARGE syndrome

Pauli, Silke; Pieper, Lasse; Häberle, Johannes; Grzmil, Paweł; Burfeind, Peter; Steckel, M; Lenz, U; Hw, Michelmann

doi:10.1111/j.1399-0004.2009.01151.x

Cited by 36 publications

(29 citation statements)

References 22 publications

(37 reference statements)

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“…Mosaicism for a p.E2546X nonsense mutation was observed in this individual's specimen. Sixteen cases of germline transmission of CHD7 mutation have been reported ( Jongmans et al, 2006;Lalani et al, 2006;Delahaye et al, 2007;Jongmans et al, 2008;Vuorela et al, 2008;Wincent et al, 2008;Pauli et al, 2009). Some of these cases involve an affected or mildly affected parent, whereas in other cases the carrier parent is reported as unaffected.…”

Section: Discussionmentioning

confidence: 99%

“…Some of these cases involve an affected or mildly affected parent, whereas in other cases the carrier parent is reported as unaffected. Two affected siblings have been reported in a family where the father had no detectable CHD7 gene mutation in lymphocyte DNA, but showed a mutation in ¼ of his sperm (Pauli et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Partial and whole gene deletions or duplications are rare, accounting for 3%-4% of pathogenic CHD7 mutations (Aramaki et al, 2006;Vuorela et al, 2007;Bergman et al, 2008;Wincent et al, 2008). Although germline transmission of CHD7 mutation has been reported (Pauli et al, 2009), the majority of mutations arise de novo.…”

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confidence: 99%

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Mutations in the CHD7 Gene: The Experience of a Commercial Laboratory

Bartels

Scacheri²,

White³

et al. 2010

Genetic Testing and Molecular Biomarkers

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CHARGE syndrome is an autosomal dominant multisystem disorder caused by mutation in the CHD7 gene, encoding chromodomain helicase DNA-binding protein 7. Molecular diagnostic testing for CHD7 mutation has been available in a clinical setting since 2005. We report here the results from the first 642 unrelated proband samples submitted for testing. Thirty-two percent (n ¼ 203) of patient samples had a heterozygous pathogenic variant identified. The lower mutation rate than that published for well-characterized clinical samples is likely due to referral bias, as samples submitted for clinical testing may be for ''rule-out'' diagnoses, rather than solely to confirm clinical suspicion. We identified 159 unique pathogenic mutations, and of these, 134 mutations were each seen in a single individual and 25 mutations were found in two to five individuals (n ¼ 69). Of the 203 mutations, only 9 were missense, with 107 nonsense, 69 frameshift, and 15 splice-site mutations likely leading to haploinsufficiency at the cellular level. An additional 72 variations identified in the 642 tested samples (11%) were considered to have unknown clinical significance. Copy number changes (deletion/duplication of the entire gene or one/several exons) were found to account for a very small number of cases (n ¼ 3). This cohort represents the largest CHARGE syndrome sample size to date and is intended to serve as a resource for clinicians, genetic counselors, researchers, and other diagnostic laboratories.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mutations in the CHD7 Gene: The Experience of a Commercial Laboratory

Bartels

Scacheri²,

White³

et al. 2010

Genetic Testing and Molecular Biomarkers

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show abstract

“…This is in agreement with previous findings suggesting that a full genetic dosage is required for complete function of CHD7 . This novel mutation was sporadic, as in most CHARGE cases described to date, therefore discarding family inheritance with asymptomatic parents [Pauli et al, 2009]. Heterozygous sequencing of DNA isolated from peripheral blood from both parents discarded somatic mosaicism, although germline mosaicism can not be discarded and could be the origin of the mutation as it has been described in similar cases .…”

Section: Discussionmentioning

confidence: 93%

Novel Frameshift CHD7 Mutation Related to CHARGE Syndrome

et al. 2013

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CHARGE syndrome is a rare congenital condition characterized by 6 cardinal features: coloboma, heart defect, atresia choanae, retarded growth and development, genital anomalies, and ear anomalies/deafness. Mutations of the chromodomain helicase DNA-binding protein gene CHD7 are reported to be a major cause of CHARGE syndrome. Herein, we report the case of a 27-year-old patient presenting with typical symptoms who bears a novel heterozygous insertion in exon 2 of the CHD7 gene (c.327dupC) resulting in an amino acid substitution and a frameshift (p.Val110Argfs*22) that leads to a 131-amino-acid truncated polypeptide, likely representing a null allele. Parental genetic screening confirmed the sporadic origin of the mutation.

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“…Germline mosaicism has been found in a variety of inherited traits (e.g. Barbosa et al, 2008, Choi et al, 2008, Fabrizi et al, 2001, Khan et al, 2010, Makri et al, 2009, Pauli et al, 2009. We use the extended statistical model to develop a parametric likelihood ratio test to evaluate whether a specific individual in a given pedigree has GM at a trait locus.…”

Section: Introductionmentioning

confidence: 99%

Genetic Linkage Analysis in the Presence of Germline Mosaicism

Weissbrod¹,

Geiger²

2011

Statistical Applications in Genetics and Molecular Biology

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Germline mosaicism is a genetic condition in which some germ cells of an individual contain a mutation. This condition violates the assumptions underlying classic genetic analysis and may lead to failure of such analysis. In this work we extend the statistical model used for genetic linkage analysis in order to incorporate germline mosaicism. We develop a likelihood ratio test for detecting whether a genetic trait has been introduced into a pedigree by germline mosaicism. We analyze the statistical properties of this test and evaluate its performance via computer simulations. We demonstrate that genetic linkage analysis has high power to identify linkage in the presence of germline mosaicism when our extended model is used. We further use this extended model to provide solid statistical evidence that the MDN syndrome studied by Genzer-Nir et al. has been introduced by germline mosaicism.

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Proven germline mosaicism in a father of two children with CHARGE syndrome

Cited by 36 publications

References 22 publications

Mutations in the CHD7 Gene: The Experience of a Commercial Laboratory

Mutations in the CHD7 Gene: The Experience of a Commercial Laboratory

Novel Frameshift CHD7 Mutation Related to CHARGE Syndrome

Genetic Linkage Analysis in the Presence of Germline Mosaicism

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