International Journal of Molecular and Cellular Medicine
مجله بین المللی سلولی و مولکولی
Int J Mol Cell Med
Medical Sciences
http://ijmcmed.org
1
admin
2251-9637
2251-9645
10.22088/IJMCM.BUMS
en
jalali
1399
8
1
gregorian
2020
11
1
9
4
online
1
fulltext
en
Investigating Genetic Factors Contributing to Variable Expressivity of Class I 17p13.3 Microduplications
Genetics & Disease
Genetics & Disease
Case Report
Case Report
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 <em>RORA</em>, <a name="_Hlk27258785">a gene already linked to autism, in the autistic boy; his sister was heterozygous for a <em>CYP1B1</em> pathogenic variant</a> that could be related to her congenital glaucoma. Besides, both siblings carried a loss-of-function variant in <em>DIP2B</em>, 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 <em>RORA</em> and <em>DIP2B</em> 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.
17p13.3 microduplication, microcephaly, neurodevelopmental disorder, autism, variable expressivity, RORA, CYP1B1, DIP2B
296
306
http://ijmcmed.org/browse.php?a_code=A-10-3184-1&slc_lang=en&sid=1
Giovanna Cantini
Tolezano
giovannactolezano@gmail.com
100319475328460019138
100319475328460019138
No
Human Genome and Stem-Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil.
Silvia Souza da
Costa
silvinha.costa@gmail.com
100319475328460019139
100319475328460019139
No
Human Genome and Stem-Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil.
Marília de Oliveira
Scliar
mariliascliar@yahoo.com.br
100319475328460019140
100319475328460019140
No
Human Genome and Stem-Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil.
Walter Luis Magalhães
Fernandes
walterlmfernandes@gmail.com
100319475328460019141
100319475328460019141
No
Department of Paediatrics, College of Medicine of Pouso Alegre, Pouso Alegre, MG, Brazil.
Paulo Alberto
Otto
otto@usp.br
100319475328460019142
100319475328460019142
No
Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil.
Débora Romeo
Bertola
debora.bertola@gmail.com
100319475328460019143
100319475328460019143
No
Human Genome and Stem-Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil.
Carla
Rosenberg
carlarosenberg2@gmail.com
100319475328460019144
100319475328460019144
No
Human Genome and Stem-Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil.
Angela Maria
Vianna-Morgante
avmorgan@ib.usp.br
100319475328460019145
100319475328460019145
No
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 Cristina Victorino
Krepischi
ana.krepischi@ib.usp.br
100319475328460019146
100319475328460019146
Yes
Human Genome and Stem-Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil.