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Case Report: Prenatal Identification of a De Novo Mosaic Neocentric Marker Resulting in 13q31.1→qter Tetrasomy in a Mildly Affected Girl

Partial tetrasomy of distal 13q has a reported association with a variable phenotype including microphthalmia, ear abnormalities, hypotelorism, facial dysmorphisms, urogenital defects, pigmentation and skin defects, and severe learning difficulties. A wide range of mosaicism has been reported, which...

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Autores principales: Dharmadhikari, Avinash V., Pereira, Elaine M., Andrews, Carli C ., Macera, Michael, Harkavy, Nina, Wapner, Ronald, Jobanputra, Vaidehi, Levy, Brynn, Ganapathi, Mythily, Liao, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343796/
https://www.ncbi.nlm.nih.gov/pubmed/35928455
http://dx.doi.org/10.3389/fgene.2022.906077
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author Dharmadhikari, Avinash V.
Pereira, Elaine M.
Andrews, Carli C .
Macera, Michael
Harkavy, Nina
Wapner, Ronald
Jobanputra, Vaidehi
Levy, Brynn
Ganapathi, Mythily
Liao, Jun
author_facet Dharmadhikari, Avinash V.
Pereira, Elaine M.
Andrews, Carli C .
Macera, Michael
Harkavy, Nina
Wapner, Ronald
Jobanputra, Vaidehi
Levy, Brynn
Ganapathi, Mythily
Liao, Jun
author_sort Dharmadhikari, Avinash V.
collection PubMed
description Partial tetrasomy of distal 13q has a reported association with a variable phenotype including microphthalmia, ear abnormalities, hypotelorism, facial dysmorphisms, urogenital defects, pigmentation and skin defects, and severe learning difficulties. A wide range of mosaicism has been reported, which may, to some extent, account for the variable spectrum of observed phenotypes. We report here a pregnancy conceived using intrauterine insemination in a 32-year-old female with a history of infertility. Non-invasive prenatal screening (NIPS) was performed in the first trimester which reported an increased risk for trisomy 13. Follow-up cytogenetic workup using chorionic villus sampling (CVS) and amniotic fluid samples showed a mosaic karyotype with a small supernumerary marker chromosome (sSMC). Chromosomal microarray analysis (CMA) identified a mosaic 31.34 Mb terminal gain on chr13q31.1q34 showing the likely origin of the sSMC to distal chromosome 13q. Follow-up metaphase FISH testing suggested an inverted duplication rearrangement involving 13q31q34 in the marker chromosome and the presence of a neocentromere. At 21 months of age, the proband has a history of gross motor delay, hypotonia, left microphthalmia, strabismus, congenital anomaly of the right optic nerve, hemangiomas, and a tethered spinal cord. Postnatal chromosome analyses in buccal, peripheral blood, and spinal cord ligament tissues were consistent with the previous amniocentesis and CVS findings, and the degree of mosaicism varied from 25 to 80%. It is often challenging to pinpoint the chromosomal identity of sSMCs using banding cytogenetics. A combination of low-pass genome sequencing of cell-free DNA, chromosomal microarray, and FISH enabled the identification of the precise chromosomal rearrangement in this patient. This study adds to the growing list of clinically identified neocentric marker chromosomes and is the first described instance of partial tetrasomy 13q31q34 identified in a mosaic state prenatally. Since NIPS is now being routinely performed along with invasive testing for advanced maternal age, an increased prenatal detection rate for mosaic sSMCs in otherwise normal pregnancies is expected. Future studies investigating how neocentromeres mediate gene expression changes could help identify potential epigenetic targets as treatment options to rescue or reverse the phenotypes seen in patients with congenital neocentromeres.
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spelling pubmed-93437962022-08-03 Case Report: Prenatal Identification of a De Novo Mosaic Neocentric Marker Resulting in 13q31.1→qter Tetrasomy in a Mildly Affected Girl Dharmadhikari, Avinash V. Pereira, Elaine M. Andrews, Carli C . Macera, Michael Harkavy, Nina Wapner, Ronald Jobanputra, Vaidehi Levy, Brynn Ganapathi, Mythily Liao, Jun Front Genet Genetics Partial tetrasomy of distal 13q has a reported association with a variable phenotype including microphthalmia, ear abnormalities, hypotelorism, facial dysmorphisms, urogenital defects, pigmentation and skin defects, and severe learning difficulties. A wide range of mosaicism has been reported, which may, to some extent, account for the variable spectrum of observed phenotypes. We report here a pregnancy conceived using intrauterine insemination in a 32-year-old female with a history of infertility. Non-invasive prenatal screening (NIPS) was performed in the first trimester which reported an increased risk for trisomy 13. Follow-up cytogenetic workup using chorionic villus sampling (CVS) and amniotic fluid samples showed a mosaic karyotype with a small supernumerary marker chromosome (sSMC). Chromosomal microarray analysis (CMA) identified a mosaic 31.34 Mb terminal gain on chr13q31.1q34 showing the likely origin of the sSMC to distal chromosome 13q. Follow-up metaphase FISH testing suggested an inverted duplication rearrangement involving 13q31q34 in the marker chromosome and the presence of a neocentromere. At 21 months of age, the proband has a history of gross motor delay, hypotonia, left microphthalmia, strabismus, congenital anomaly of the right optic nerve, hemangiomas, and a tethered spinal cord. Postnatal chromosome analyses in buccal, peripheral blood, and spinal cord ligament tissues were consistent with the previous amniocentesis and CVS findings, and the degree of mosaicism varied from 25 to 80%. It is often challenging to pinpoint the chromosomal identity of sSMCs using banding cytogenetics. A combination of low-pass genome sequencing of cell-free DNA, chromosomal microarray, and FISH enabled the identification of the precise chromosomal rearrangement in this patient. This study adds to the growing list of clinically identified neocentric marker chromosomes and is the first described instance of partial tetrasomy 13q31q34 identified in a mosaic state prenatally. Since NIPS is now being routinely performed along with invasive testing for advanced maternal age, an increased prenatal detection rate for mosaic sSMCs in otherwise normal pregnancies is expected. Future studies investigating how neocentromeres mediate gene expression changes could help identify potential epigenetic targets as treatment options to rescue or reverse the phenotypes seen in patients with congenital neocentromeres. Frontiers Media S.A. 2022-07-19 /pmc/articles/PMC9343796/ /pubmed/35928455 http://dx.doi.org/10.3389/fgene.2022.906077 Text en Copyright © 2022 Dharmadhikari, Pereira, Andrews, Macera, Harkavy, Wapner, Jobanputra, Levy, Ganapathi and Liao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Dharmadhikari, Avinash V.
Pereira, Elaine M.
Andrews, Carli C .
Macera, Michael
Harkavy, Nina
Wapner, Ronald
Jobanputra, Vaidehi
Levy, Brynn
Ganapathi, Mythily
Liao, Jun
Case Report: Prenatal Identification of a De Novo Mosaic Neocentric Marker Resulting in 13q31.1→qter Tetrasomy in a Mildly Affected Girl
title Case Report: Prenatal Identification of a De Novo Mosaic Neocentric Marker Resulting in 13q31.1→qter Tetrasomy in a Mildly Affected Girl
title_full Case Report: Prenatal Identification of a De Novo Mosaic Neocentric Marker Resulting in 13q31.1→qter Tetrasomy in a Mildly Affected Girl
title_fullStr Case Report: Prenatal Identification of a De Novo Mosaic Neocentric Marker Resulting in 13q31.1→qter Tetrasomy in a Mildly Affected Girl
title_full_unstemmed Case Report: Prenatal Identification of a De Novo Mosaic Neocentric Marker Resulting in 13q31.1→qter Tetrasomy in a Mildly Affected Girl
title_short Case Report: Prenatal Identification of a De Novo Mosaic Neocentric Marker Resulting in 13q31.1→qter Tetrasomy in a Mildly Affected Girl
title_sort case report: prenatal identification of a de novo mosaic neocentric marker resulting in 13q31.1→qter tetrasomy in a mildly affected girl
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343796/
https://www.ncbi.nlm.nih.gov/pubmed/35928455
http://dx.doi.org/10.3389/fgene.2022.906077
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