LRBA Deficiency in a Patient With a Novel Homozygous Mutation Due to Chromosome 4 Segmental Uniparental Isodisomy

LRBA deficiency was first described in 2012 as an autosomal recessive disorder caused by biallelic mutations in the LRBA gene (OMIM #614700). It was initially characterized as producing early-onset hypogammaglobulinemia, autoimmune manifestations, susceptibility to inflammatory bowel disease, and re...

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Autores: Soler-Palacín, Pere|||0000-0002-0346-5570, Garcia-Prat, Marina|||0000-0001-5387-1908, Martín-Nalda, Andrea|||0000-0002-1715-153X, Franco-Jarava, Clara|||0000-0002-9788-189X, Rivière, Jacques G.|||0000-0003-1055-2063, Plaja Rustein, Alberto|||0000-0002-2398-1134, Bezdan, Daniela, Bosio, Mattia, Martínez Gallo, Mónica|||0000-0002-7340-2161, Ossowski, Stephan|||0000-0002-7416-9568, Colobrán Oriol, Roger|||0000-0002-5964-536X
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:253708
Acceso en línea:https://ddd.uab.cat/record/253708
https://dx.doi.org/urn:doi:10.3389/fimmu.2018.02397
Access Level:acceso abierto
Palabra clave:Primary immunodeficiency
LRBA deficiency
Uniparental disomy
Whole exome sequencing
Comparative genomic hybridization array
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spelling LRBA Deficiency in a Patient With a Novel Homozygous Mutation Due to Chromosome 4 Segmental Uniparental IsodisomySoler-Palacín, Pere|||0000-0002-0346-5570Garcia-Prat, Marina|||0000-0001-5387-1908Martín-Nalda, Andrea|||0000-0002-1715-153XFranco-Jarava, Clara|||0000-0002-9788-189XRivière, Jacques G.|||0000-0003-1055-2063Plaja Rustein, Alberto|||0000-0002-2398-1134Bezdan, DanielaBosio, MattiaMartínez Gallo, Mónica|||0000-0002-7340-2161Ossowski, Stephan|||0000-0002-7416-9568Colobrán Oriol, Roger|||0000-0002-5964-536XPrimary immunodeficiencyLRBA deficiencyUniparental disomyWhole exome sequencingComparative genomic hybridization arrayLRBA deficiency was first described in 2012 as an autosomal recessive disorder caused by biallelic mutations in the LRBA gene (OMIM #614700). It was initially characterized as producing early-onset hypogammaglobulinemia, autoimmune manifestations, susceptibility to inflammatory bowel disease, and recurrent infection. However, further reports expanded this phenotype (including patients without hypogammaglobulinemia) and described LRBA deficiency as a clinically variable syndrome with a wide spectrum of clinical manifestations. We present the case of a female patient who presented with type 1 diabetes, psoriasis, oral thrush, and enlarged liver and spleen at the age of 8 months. She later experienced recurrent bacterial and viral infections, including pneumococcal meningitis and Epstein Barr viremia. She underwent two consecutive stem cell transplants at the age of 8 and 9 years, and ultimately died. Samples from the patient and her parents were subjected to whole exome sequencing, which revealed a homozygous 1-bp insertion in exon 23 of the patient's LRBA gene, resulting in frameshift and premature stop codon. The patient's healthy mother was heterozygous for the mutation and her father tested wild-type. This finding suggested that either one copy of the paternal chromosome 4 bore a deletion including the LRBA locus, or the patient inherited two copies of the mutant maternal LRBA allele. The patient's sequencing data showed a 1-Mb loss of heterozygosity region in chromosome 4, including the LRBA gene. Comparative genomic hybridization array of the patient's and father's genomic DNA yielded normal findings, ruling out genomic copy number abnormalities. Here, we present the first case of LRBA deficiency due to a uniparental disomy (UPD). In contrast to classical Mendelian inheritance, UPD involves inheritance of 2 copies of a chromosomal region from only 1 parent. Specifically, our patient carried a small segmental isodisomy of maternal origin affecting 1 Mb of chromosome 4.Universitat Autònoma de Barcelona 22018-01-0120182018-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/253708https://dx.doi.org/urn:doi:10.3389/fimmu.2018.02397reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengMinisterio de Ciencia e Innovación https://doi.org/10.13039/501100004837 PI11/01086Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 PI14/00405Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI17/00660open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2537082026-06-06T12:50:31Z
dc.title.none.fl_str_mv LRBA Deficiency in a Patient With a Novel Homozygous Mutation Due to Chromosome 4 Segmental Uniparental Isodisomy
title LRBA Deficiency in a Patient With a Novel Homozygous Mutation Due to Chromosome 4 Segmental Uniparental Isodisomy
spellingShingle LRBA Deficiency in a Patient With a Novel Homozygous Mutation Due to Chromosome 4 Segmental Uniparental Isodisomy
Soler-Palacín, Pere|||0000-0002-0346-5570
Primary immunodeficiency
LRBA deficiency
Uniparental disomy
Whole exome sequencing
Comparative genomic hybridization array
title_short LRBA Deficiency in a Patient With a Novel Homozygous Mutation Due to Chromosome 4 Segmental Uniparental Isodisomy
title_full LRBA Deficiency in a Patient With a Novel Homozygous Mutation Due to Chromosome 4 Segmental Uniparental Isodisomy
title_fullStr LRBA Deficiency in a Patient With a Novel Homozygous Mutation Due to Chromosome 4 Segmental Uniparental Isodisomy
title_full_unstemmed LRBA Deficiency in a Patient With a Novel Homozygous Mutation Due to Chromosome 4 Segmental Uniparental Isodisomy
title_sort LRBA Deficiency in a Patient With a Novel Homozygous Mutation Due to Chromosome 4 Segmental Uniparental Isodisomy
dc.creator.none.fl_str_mv Soler-Palacín, Pere|||0000-0002-0346-5570
Garcia-Prat, Marina|||0000-0001-5387-1908
Martín-Nalda, Andrea|||0000-0002-1715-153X
Franco-Jarava, Clara|||0000-0002-9788-189X
Rivière, Jacques G.|||0000-0003-1055-2063
Plaja Rustein, Alberto|||0000-0002-2398-1134
Bezdan, Daniela
Bosio, Mattia
Martínez Gallo, Mónica|||0000-0002-7340-2161
Ossowski, Stephan|||0000-0002-7416-9568
Colobrán Oriol, Roger|||0000-0002-5964-536X
author Soler-Palacín, Pere|||0000-0002-0346-5570
author_facet Soler-Palacín, Pere|||0000-0002-0346-5570
Garcia-Prat, Marina|||0000-0001-5387-1908
Martín-Nalda, Andrea|||0000-0002-1715-153X
Franco-Jarava, Clara|||0000-0002-9788-189X
Rivière, Jacques G.|||0000-0003-1055-2063
Plaja Rustein, Alberto|||0000-0002-2398-1134
Bezdan, Daniela
Bosio, Mattia
Martínez Gallo, Mónica|||0000-0002-7340-2161
Ossowski, Stephan|||0000-0002-7416-9568
Colobrán Oriol, Roger|||0000-0002-5964-536X
author_role author
author2 Garcia-Prat, Marina|||0000-0001-5387-1908
Martín-Nalda, Andrea|||0000-0002-1715-153X
Franco-Jarava, Clara|||0000-0002-9788-189X
Rivière, Jacques G.|||0000-0003-1055-2063
Plaja Rustein, Alberto|||0000-0002-2398-1134
Bezdan, Daniela
Bosio, Mattia
Martínez Gallo, Mónica|||0000-0002-7340-2161
Ossowski, Stephan|||0000-0002-7416-9568
Colobrán Oriol, Roger|||0000-0002-5964-536X
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universitat Autònoma de Barcelona
dc.subject.none.fl_str_mv Primary immunodeficiency
LRBA deficiency
Uniparental disomy
Whole exome sequencing
Comparative genomic hybridization array
topic Primary immunodeficiency
LRBA deficiency
Uniparental disomy
Whole exome sequencing
Comparative genomic hybridization array
description LRBA deficiency was first described in 2012 as an autosomal recessive disorder caused by biallelic mutations in the LRBA gene (OMIM #614700). It was initially characterized as producing early-onset hypogammaglobulinemia, autoimmune manifestations, susceptibility to inflammatory bowel disease, and recurrent infection. However, further reports expanded this phenotype (including patients without hypogammaglobulinemia) and described LRBA deficiency as a clinically variable syndrome with a wide spectrum of clinical manifestations. We present the case of a female patient who presented with type 1 diabetes, psoriasis, oral thrush, and enlarged liver and spleen at the age of 8 months. She later experienced recurrent bacterial and viral infections, including pneumococcal meningitis and Epstein Barr viremia. She underwent two consecutive stem cell transplants at the age of 8 and 9 years, and ultimately died. Samples from the patient and her parents were subjected to whole exome sequencing, which revealed a homozygous 1-bp insertion in exon 23 of the patient's LRBA gene, resulting in frameshift and premature stop codon. The patient's healthy mother was heterozygous for the mutation and her father tested wild-type. This finding suggested that either one copy of the paternal chromosome 4 bore a deletion including the LRBA locus, or the patient inherited two copies of the mutant maternal LRBA allele. The patient's sequencing data showed a 1-Mb loss of heterozygosity region in chromosome 4, including the LRBA gene. Comparative genomic hybridization array of the patient's and father's genomic DNA yielded normal findings, ruling out genomic copy number abnormalities. Here, we present the first case of LRBA deficiency due to a uniparental disomy (UPD). In contrast to classical Mendelian inheritance, UPD involves inheritance of 2 copies of a chromosomal region from only 1 parent. Specifically, our patient carried a small segmental isodisomy of maternal origin affecting 1 Mb of chromosome 4.
publishDate 2018
dc.date.none.fl_str_mv 2
2018-01-01
2018
2018-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/253708
https://dx.doi.org/urn:doi:10.3389/fimmu.2018.02397
url https://ddd.uab.cat/record/253708
https://dx.doi.org/urn:doi:10.3389/fimmu.2018.02397
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Ministerio de Ciencia e Innovación https://doi.org/10.13039/501100004837 PI11/01086
Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 PI14/00405
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI17/00660
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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