Exploring the Genetic Causality of Discordant Phenotypes in Familial Apparently Balanced Translocation Cases Using Whole Exome Sequencing.

Autor:	Aristidou C; Department of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus., Theodosiou A; Department of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus., Alexandrou A; Department of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus., Papaevripidou I; Department of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus., Evangelidou P; Department of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus., Kosmaidou-Aravidou Z; Department of Genetics, Alexandra Hospital, 11528 Athens, Greece., Behjati F; Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran 1985713871, Iran., Christophidou-Anastasiadou V; Department of Clinical Genetics, Archbishop Makarios III Medical Centre, 2012 Nicosia, Cyprus.; Department of Clinical Genetics and Genomics, The Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus., Tanteles GA; Department of Clinical Genetics and Genomics, The Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus., Sismani C; Department of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus.
Jazyk:	angličtina
Zdroj:	Genes [Genes (Basel)] 2022 Dec 27; Vol. 14 (1). Date of Electronic Publication: 2022 Dec 27.
DOI:	10.3390/genes14010082
Abstrakt:	Familial apparently balanced translocations (ABTs) are usually not associated with a phenotype; however, rarely, ABTs segregate with discordant phenotypes in family members carrying identical rearrangements. The current study was a follow-up investigation of four familial ABTs, where whole exome sequencing (WES) was implemented as a diagnostic tool to identify the underlying genetic aetiology of the patients' phenotypes. Data were analysed using an in-house bioinformatics pipeline alongside VarSome Clinical. WES findings were validated with Sanger sequencing, while the impact of splicing and missense variants was assessed by reverse-transcription PCR and in silico tools, respectively. Novel candidate variants were identified in three families. In family 1, it was shown that the de novo pathogenic STXBP1 variant (NM_003165.6:c.1110+2T>G) affected splicing and segregated with the patient's phenotype. In family 2, a likely pathogenic TUBA1A variant (NM_006009.4:c.875C>T, NP_006000.2:p.(Thr292Ile)) could explain the patient's symptoms. In family 3, an SCN1A variant of uncertain significance (NM_006920.6:c.5060A>G, NP_008851.3:p.(Glu1687Gly)) required additional evidence to sufficiently support causality. This first report of WES application in familial ABT carriers with discordant phenotypes supported our previous findings describing such rearrangements as coincidental. Thus, WES can be recommended as a complementary test to find the monogenic cause of aberrant phenotypes in familial ABT carriers. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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