Dataset Information

Genetic Counselling Pitfall: Co-Occurrence of an 11.8-Mb Xp22 Duplication and an Xp21.2 Duplication Disrupting IL1RAPL1.

ABSTRACT: We report a 3-generation family in which 2 Xp copy number variations (CNVs) co-segregate. The proband presented with syndromic intellectual disability. The CNV had been revealed by conventional karyotyping, identifying a large Xp22 duplication causing an Xp functional disomy. Family studies found that this duplication was inherited from the proband's mother and was also present in one of his sisters. This sister had conventional karyotyping performed during pregnancy with a normal result. Postnatally, her child, the proband's nephew, presented with autism spectrum disorders. aCGH revealed a 339-kb IL1RAPL1 duplication. Overall, the proband, his mother, and one of his sisters all harboured both CNVs, while his other sister and the 2 sons of each sister only carried the IL1RAPL1 intragenic duplication. As seen in this family, we emphasise the importance of small CNV detection, the pathogenicity of IL1RAPL1 exonic duplications in male carriers, and the difficulties for genetic counselling with the risk of double diagnosis in a single patient.

SUBMITTER: Chatron N

PROVIDER: S-EPMC5701268 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Genetic Counselling Pitfall: Co-Occurrence of an 11.8-Mb Xp22 Duplication and an Xp21.2 Duplication Disrupting <i>IL1RAPL1</i>.

Chatron Nicolas N Thibault Lucie L Lespinasse James J Labalme Audrey A Schluth-Bolard Caroline C Till Marianne M Edery Patrick P Touraine Renaud R des Portes Vincent V Lesca Gaetan G Sanlaville Damien D

Molecular syndromology 20170907 6

We report a 3-generation family in which 2 Xp copy number variations (CNVs) co-segregate. The proband presented with syndromic intellectual disability. The CNV had been revealed by conventional karyotyping, identifying a large Xp22 duplication causing an Xp functional disomy. Family studies found that this duplication was inherited from the proband's mother and was also present in one of his sisters. This sister had conventional karyotyping performed during pregnancy with a normal result. Postna ...[more]

PMID: 29230163

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Project description:IMPORTANCE:?-Synuclein (SNCA) locus duplications are associated with variable clinical features and reduced penetrance but the reasons underlying this variability are unknown. OBJECTIVES:To report a novel family carrying a heterozygous 6.4 Mb duplication of the SNCA locus with an atypical clinical presentation strongly reminiscent of frontotemporal dementia and late-onset pallidopyramidal syndromes and study phenotype-genotype correlations in SNCA locus duplications. DESIGN, SETTING, AND PARTICIPANTS:We report the clinical and neuropathologic features of a family carrying a 6.4 Mb duplication of the SNCA locus. To identify candidate disease modifiers, we completed a genetic analysis of the family and conducted statistical analysis on previously published cases carrying SNCA locus duplications using regression modeling with robust standard errors to account for clustering at the family level. MAIN OUTCOMES AND MEASURES:We assessed whether length of the SNCA locus duplication influences disease penetrance and severity and whether extraduplication factors have a disease-modifying role. RESULTS:We identified a large 6.4 Mb duplication of the SNCA locus in this family. Neuropathological analysis showed extensive ?-synuclein pathology with minimal phospho-tau pathology. Genetic analysis showed an increased burden of Parkinson disease-related risk factors and the disease-predisposing H1/H1 microtubule-associated protein tau haplotype. Statistical analysis of previously published cases suggested there is a trend toward increasing disease severity and disease penetrance with increasing duplication size. The corresponding odds ratios from the univariable analyses were 1.17 (95% CI, 0.81-1.68) and 1.34 (95% CI, 0.78-2.31), respectively. Sex was significantly associated with both disease risk and severity; men compared with women had increased disease risk and severity and the corresponding odds ratios from the univariable analyses were 8.36 (95% CI, 1.97-35.42) and 5.55 (95% CI, 1.39-22.22), respectively. CONCLUSIONS AND RELEVANCE:These findings further expand the phenotypic spectrum of SNCA locus duplications. Increased dosage of genes located within the duplicated region probably cannot increase disease risk and disease severity without the contribution of additional risk factors. Identification of disease modifiers accounting for the substantial phenotypic heterogeneity of patients with SNCA locus duplications could provide insight into molecular events involved in ?-synuclein aggregation.

Dataset Information

Genetic Counselling Pitfall: Co-Occurrence of an 11.8-Mb Xp22 Duplication and an Xp21.2 Duplication Disrupting IL1RAPL1.

Publications

Genetic Counselling Pitfall: Co-Occurrence of an 11.8-Mb Xp22 Duplication and an Xp21.2 Duplication Disrupting <i>IL1RAPL1</i>.

Similar Datasets

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