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A de novo nonsense mutation in ASXL3 shared by siblings with Bainbridge–Ropers syndrome

Two sisters (ages 16 yr and 15 yr) have been followed by our clinical genetics team for several years. Both girls have severe intellectual disability, hypotonia, seizures, and distinctive craniofacial features. The parents are healthy and have no other children. Oligo array, fragile X testing, and n...

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Autores principales: Koboldt, Daniel C., Mihalic Mosher, Theresa, Kelly, Benjamin J., Sites, Emily, Bartholomew, Dennis, Hickey, Scott E., McBride, Kim, Wilson, Richard K., White, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983172/
https://www.ncbi.nlm.nih.gov/pubmed/29305346
http://dx.doi.org/10.1101/mcs.a002410
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author Koboldt, Daniel C.
Mihalic Mosher, Theresa
Kelly, Benjamin J.
Sites, Emily
Bartholomew, Dennis
Hickey, Scott E.
McBride, Kim
Wilson, Richard K.
White, Peter
author_facet Koboldt, Daniel C.
Mihalic Mosher, Theresa
Kelly, Benjamin J.
Sites, Emily
Bartholomew, Dennis
Hickey, Scott E.
McBride, Kim
Wilson, Richard K.
White, Peter
author_sort Koboldt, Daniel C.
collection PubMed
description Two sisters (ages 16 yr and 15 yr) have been followed by our clinical genetics team for several years. Both girls have severe intellectual disability, hypotonia, seizures, and distinctive craniofacial features. The parents are healthy and have no other children. Oligo array, fragile X testing, and numerous single-gene tests were negative. All four family members underwent research exome sequencing, which revealed a heterozygous nonsense mutation in ASXL3 (p.R1036X) that segregated with disease. Exome data and independent Sanger sequencing confirmed that the variant is de novo, suggesting possible germline mosaicism in one parent. The p.R1036X variant has never been observed in healthy human populations and has been previously reported as a pathogenic mutation. Truncating de novo mutations in ASXL3 cause Bainbridge–Ropers syndrome (BRPS), a developmental disorder with similarities to Bohring–Opitz syndrome. Fewer than 30 BRPS patients have been described in the literature; to our knowledge, this is the first report of the disorder in two related individuals. Our findings lend further support to intellectual disability, absent speech, autistic traits, hypotonia, and distinctive facial appearance as common emerging features of Bainbridge–Ropers syndrome.
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spelling pubmed-59831722018-06-08 A de novo nonsense mutation in ASXL3 shared by siblings with Bainbridge–Ropers syndrome Koboldt, Daniel C. Mihalic Mosher, Theresa Kelly, Benjamin J. Sites, Emily Bartholomew, Dennis Hickey, Scott E. McBride, Kim Wilson, Richard K. White, Peter Cold Spring Harb Mol Case Stud Rapid Communication Two sisters (ages 16 yr and 15 yr) have been followed by our clinical genetics team for several years. Both girls have severe intellectual disability, hypotonia, seizures, and distinctive craniofacial features. The parents are healthy and have no other children. Oligo array, fragile X testing, and numerous single-gene tests were negative. All four family members underwent research exome sequencing, which revealed a heterozygous nonsense mutation in ASXL3 (p.R1036X) that segregated with disease. Exome data and independent Sanger sequencing confirmed that the variant is de novo, suggesting possible germline mosaicism in one parent. The p.R1036X variant has never been observed in healthy human populations and has been previously reported as a pathogenic mutation. Truncating de novo mutations in ASXL3 cause Bainbridge–Ropers syndrome (BRPS), a developmental disorder with similarities to Bohring–Opitz syndrome. Fewer than 30 BRPS patients have been described in the literature; to our knowledge, this is the first report of the disorder in two related individuals. Our findings lend further support to intellectual disability, absent speech, autistic traits, hypotonia, and distinctive facial appearance as common emerging features of Bainbridge–Ropers syndrome. Cold Spring Harbor Laboratory Press 2018-06 /pmc/articles/PMC5983172/ /pubmed/29305346 http://dx.doi.org/10.1101/mcs.a002410 Text en © 2018 Koboldt et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
spellingShingle Rapid Communication
Koboldt, Daniel C.
Mihalic Mosher, Theresa
Kelly, Benjamin J.
Sites, Emily
Bartholomew, Dennis
Hickey, Scott E.
McBride, Kim
Wilson, Richard K.
White, Peter
A de novo nonsense mutation in ASXL3 shared by siblings with Bainbridge–Ropers syndrome
title A de novo nonsense mutation in ASXL3 shared by siblings with Bainbridge–Ropers syndrome
title_full A de novo nonsense mutation in ASXL3 shared by siblings with Bainbridge–Ropers syndrome
title_fullStr A de novo nonsense mutation in ASXL3 shared by siblings with Bainbridge–Ropers syndrome
title_full_unstemmed A de novo nonsense mutation in ASXL3 shared by siblings with Bainbridge–Ropers syndrome
title_short A de novo nonsense mutation in ASXL3 shared by siblings with Bainbridge–Ropers syndrome
title_sort de novo nonsense mutation in asxl3 shared by siblings with bainbridge–ropers syndrome
topic Rapid Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983172/
https://www.ncbi.nlm.nih.gov/pubmed/29305346
http://dx.doi.org/10.1101/mcs.a002410
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