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Investigating Genetic Factors Contributing to Variable Expressivity of Class I 17p13.3 Microduplications
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Giovanna Cantini Tolezano1    , Silvia Souza da Costa1 , Marília de Oliveira Scliar1 , Walter Luis Magalhães Fernandes2 , Paulo Alberto Otto3 , Débora Romeo Bertola1 , Carla Rosenberg1 , Angela Maria Vianna-Morgante1 , Ana Cristina Victorino Krepischi 4 |
1- Human Genome and Stem-Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil.
2- Department of Paediatrics, College of Medicine of Pouso Alegre, Pouso Alegre, MG, Brazil.
3- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil.
4- Human Genome and Stem-Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil. , ana.krepischi@ib.usp.br |
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Abstract: (3619 Views) |
| 17p13.3 microduplications are rare copy number variations (CNVs) associated with variable phenotypes, including facial dysmorphism, developmental delay, intellectual disability, and autism. Typically, when a recognized pathogenic CNV is identified, other genetic factors are not considered. We investigated via whole-exome sequencing the presence of additional variants in four carriers of class I 17p13.3 microduplications. A 730 kb 17p13.3 microduplication was identified in two half-brothers with intellectual disability, but not in a third affected half-brother or blood cells from their normal mother (Family A), thus leading to the hypothesis of maternal germline mosaicism. No additional pathogenic variants were detected in Family A. Two affected siblings carried maternally inherited 450 kb 17p13.3 microduplication (Family B); the three carriers of the microduplication exhibited microcephaly and learning disability/speech impairment of variable degrees. Exome analysis revealed a variant of uncertain significance in RORA, a gene already linked to autism, in the autistic boy; his sister was heterozygous for a CYP1B1 pathogenic variant that could be related to her congenital glaucoma. Besides, both siblings carried a loss-of-function variant in DIP2B, a candidate gene for intellectual disability, which was inherited from their father, who also exhibited learning disability in childhood. In conclusion, additional pathogenic variants were revealed in two affected carriers of class I 17p13.3 microduplication (Family B), probably adding to their phenotypes. These results provided new evidence regarding the contribution of RORA and DIP2B to neurocognitive deficits, and highlighted the importance of full genetic investigation in carriers of CNV syndromes with variable expressivity. Finally, we suggest that microcephaly may be a rare clinical feature also related to the presence of the class I 17p13.3 microduplication. |
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| Keywords: 17p13.3 microduplication, microcephaly, neurodevelopmental disorder, autism, variable expressivity, RORA, CYP1B1, DIP2B |
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Full-Text [PDF 436 kb]
(1486 Downloads)
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Type of Study: Case Report |
Subject:
Genetics & Disease
Received: 2020/10/23 | Accepted: 2021/01/2 | Published: 2020/11/30
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Tolezano G C, Costa S S D, Scliar M D O, Fernandes W L M, Otto P A, Bertola D R, et al . Investigating Genetic Factors Contributing to Variable Expressivity of Class I 17p13.3 Microduplications. Int J Mol Cell Med 2020; 9 (4) :296-306 URL: http://ijmcmed.org/article-1-1491-en.html
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