Unmasking of a Recessive SCARF2 Mutation by a 22q11.12 de novo Deletion in a Patient with Van den Ende-Gupta Syndrome

Bedeschi, Mf; Colombo, Lorenzo; Mari, Francesca; Hofmann, Kristin; Rauch, Anita; Gentilin, Barbara; Renieri, Alessandra; Clerici, Dariane Jornada

doi:10.1159/000328135

Cited by 33 publications

(40 citation statements)

References 31 publications

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“…Of the 24 cases with a deletion, 11 involved a known recurrent CNV. This is in agreement with frequent suggestions in the literature that the phenotypic variability of patients with a recurrent CNV may be due to an MMM, such as unmasking [Mefford et al, 2008;Hannes et al, 2009;Kumar et al, 2009;Bedeschi et al, 2010;Kunishima et al, 2013;McDonald-McGinn et al, 2013]. For 5 of the 11 de novo CNVs, the parental origin of the rearrangement could be determined: 4 occurred in the germ line of the father.…”

Section: Mixed Mutation Mechanismssupporting

confidence: 90%

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

Poot

Haaf

2015

Mol Syndromol

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Complex chromosome rearrangements (CCRs) are currently defined as structural genome variations that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. They are thought to be extremely rare, but their detection rate is rising because of improvements in molecular cytogenetic technology. Their population frequency is also underestimated, since many CCRs may not elicit a phenotypic effect. CCRs may be the result of fork stalling and template switching, microhomology-mediated break-induced repair, breakage-fusion-bridge cycles, or chromothripsis. Patients with chromosomal instability syndromes show elevated rates of CCRs due to impaired DNA double-strand break responses during meiosis. Therefore, the putative functions of the proteins encoded by ATM, BLM, WRN, ATR, MRE11, NBS1, and RAD51 in preventing CCRs are discussed. CCRs may exert a pathogenic effect by either (1) gene dosage-dependent mechanisms, e.g. haploinsufficiency, (2) mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and thus their interactions disturbed - these mechanisms will predominantly affect gene expression - or (3) mixed mutation mechanisms in which a CCR on one chromosome is combined with a different type of mutation on the other chromosome. Such inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. Also, future studies with in vitro models, such as inducible pluripotent stem cells from patients with CCRs, and transgenic model organisms should substantiate current inferences regarding putative pathogenic effects of CCRs. The ramifications of the growing body of information on CCRs for clinical and experimental genetics and future treatment modalities are briefly illustrated with 2 cases, one of which suggests KDM4C(JMJD2C) as a novel candidate gene for mental retardation.

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Section: Mixed Mutation Mechanismssupporting

confidence: 90%

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

Poot

Haaf

2015

Mol Syndromol

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“…Thus, it's a question whether deafness is a part of CdLS or another disease apart from CdLS. As ARNSHL is an autosomal recessive genetic disease and there is one chromosome microdeletion in our patient, so if the hearing disorder were caused by ARNSHL, there must be a mutation of the DFNB31 in the other chromosome [36]. Keeping this in mind, we searched for the mutations of DFNB31 in our patient.…”

Section: Discussionmentioning

confidence: 99%

Patients Carrying 9q31.1-q32 Deletion Share Common Features with Cornelia de Lange Syndrome

Cao

Tian

Fang

et al. 2015

Cell Physiol Biochem

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Background: Cornelia de Lange Syndrome (CdLS) is a rare but severe clinically heterogeneous developmental disorder characterized by facial dysmorphia, growth and cognitive retardation, and abnormalities of limb development. Objectives: To determine the pathogenesis of a patient with CdLS. Methods: We studied a patient with CdLS by whole exome sequencing, karyotyping and Agilent CGH Array. The results were confirmed by quantitative real-time PCR analysis of the patient and her parents. Further comparison of our patient and cases with partially overlapping deletions retrieved from the literature and databases was undertaken. Results: Whole exome sequencing had excluded the mutation of cohesion genes such as NIPBL,SMC1A and SMC3. The result of karyotyping showed a deletion of chromosome 9q31.1-q32 and the result of Agilent CGH Array further displayed a 12.01-Mb region of deletion at chromosome bands 9q31.1-q32. Reported cases with the deletion of 9q31.1-q32 share similar features with our CdLS patient. One of the genes in the deleted region, SMC2, belongs to the Structural Maintenance of Chromosomes (SMC) family and regulates gene expression and DNA repair. Conclusions: Patients carrying the deletion of 9q31.1-q32 showed similar phenotypes with CdLS.

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“…Correlation of phenotype to specific genes in large microdeletions is often a very difficult effort, but one mechanism by which a chromosome microdeletion can give rise to at least part of the phenotype is through unmasking an inherited recessive mutation [Bedeschi et al, 2010]. Keeping this in mind, we sequenced the FKTN gene, which causes Fukuyama Congenital Muscular Dystrophy in patients who carry two null mutations [Kobayashi et al, 1998], but also DCM with minimal muscle involvement in patients who carry a null allele and a missense (hypomorphic) variant on the second allele [Murakami et al, 2006].…”

Section: Discussionmentioning

confidence: 99%

9q31.1q31.3 deletion in two patients with similar clinical features: A newly recognized microdeletion syndrome?

Mucciolo

Magini

Marozza

et al. 2013

American J of Med Genetics Pt A

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Interstitial deletions of the long arm of chromosome 9 are rare and most patients have been detected by conventional cytogenetic techniques. Disparities in size and localization are large and no consistent region of overlap has been delineated. We report two similar de novo deletions of 6.3 Mb involving the 9q31.1q31.3 region, identified in two monozygotic twins and one unrelated patient through array-CGH analysis. By cloning the deletion breakpoints, we could show that these deletions are not mediated by segmental duplications. The patients displayed a distinct clinical phenotype characterized by mild intellectual disability, short stature with high body mass index, thick hair, arched eyebrows, flat profile with broad chin and mild prognathism, broad, and slightly overhanging tip of the nose, short neck with cervical gibbus. The twin patients developed a metabolic syndrome (type 2 diabetes, hypercholesterolemia, vascular hypertension) during the third decade of life. Although long-term follow-up and collection of additional patients will be needed to obtain a better definition of the phenotype, our findings characterize a previously undescribed syndromic disorder associated with haploinsufficiency of the chromosome 9q31.1q31.3 region.

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Unmasking of a Recessive SCARF2 Mutation by a 22q11.12 de novo Deletion in a Patient with Van den Ende-Gupta Syndrome

Cited by 33 publications

References 31 publications

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

Patients Carrying 9q31.1-q32 Deletion Share Common Features with Cornelia de Lange Syndrome

9q31.1q31.3 deletion in two patients with similar clinical features: A newly recognized microdeletion syndrome?

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