TY - JOUR
T1 - Case Report
T2 - Partial Uniparental Disomy Unmasks a Novel Recessive Mutation in the LYST Gene in a Patient With a Severe Phenotype of Chédiak-Higashi Syndrome
AU - Boluda-Navarro, Mireia
AU - Ibáñez, Mariam
AU - Liquori, Alessandro
AU - Franco-Jarava, Clara
AU - Martínez-Gallo, Mónica
AU - Rodríguez-Vega, Héctor
AU - Teresa, Jaijo
AU - Carreras, Carmen
AU - Such, Esperanza
AU - Zúñiga, Ángel
AU - Colobran, Roger
AU - Cervera, José Vicente
N1 - Publisher Copyright:
© Copyright © 2021 Boluda-Navarro, Ibáñez, Liquori, Franco-Jarava, Martínez-Gallo, Rodríguez-Vega, Teresa, Carreras, Such, Zúñiga, Colobran and Cervera.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/3/31
Y1 - 2021/3/31
N2 - Chédiak-Higashi syndrome (CHS) is a rare autosomal recessive (AR) immune disorder that has usually been associated to missense, nonsense or indels mutations in the LYST gene. In this study, we describe for the first time the case of a CHS patient carrying a homozygous mutation in the LYST gene inherited as a result of a partial uniparental isodisomy (UPiD) of maternal origin. Sanger sequencing of the LYST cDNA and single nucleotide polymorphism (SNP)-arrays were performed to identify the causative mutation and to explain the molecular mechanism of inheritance, respectively. Partial-UPiD leads to a copy neutral loss of heterozygosity (CN-LOH) of the telomeric region of chromosome 1 (1q41q44), unmasking the potential effect of the mutation detected. The mutation (c.8380dupT) is an insertion located in exon 32 of the LYST gene resulting in a premature stop codon and leading to the loss of all the conserved domains at the C-terminal of the LYST protein. This would account for the severe phenotype observed. We also reviewed the only two previously reported cases of CHS as a result of a uniparental disomy. In this study, we show that the combination of different strategies, including the use of SNP-arrays, is pivotal to fine-tune the diagnosis of rare AR disorders, such as CHS. Moreover, this case highlights the relevance of uniparental disomy as a potential mechanism of CHS expression in non-consanguineous families.
AB - Chédiak-Higashi syndrome (CHS) is a rare autosomal recessive (AR) immune disorder that has usually been associated to missense, nonsense or indels mutations in the LYST gene. In this study, we describe for the first time the case of a CHS patient carrying a homozygous mutation in the LYST gene inherited as a result of a partial uniparental isodisomy (UPiD) of maternal origin. Sanger sequencing of the LYST cDNA and single nucleotide polymorphism (SNP)-arrays were performed to identify the causative mutation and to explain the molecular mechanism of inheritance, respectively. Partial-UPiD leads to a copy neutral loss of heterozygosity (CN-LOH) of the telomeric region of chromosome 1 (1q41q44), unmasking the potential effect of the mutation detected. The mutation (c.8380dupT) is an insertion located in exon 32 of the LYST gene resulting in a premature stop codon and leading to the loss of all the conserved domains at the C-terminal of the LYST protein. This would account for the severe phenotype observed. We also reviewed the only two previously reported cases of CHS as a result of a uniparental disomy. In this study, we show that the combination of different strategies, including the use of SNP-arrays, is pivotal to fine-tune the diagnosis of rare AR disorders, such as CHS. Moreover, this case highlights the relevance of uniparental disomy as a potential mechanism of CHS expression in non-consanguineous families.
KW - CHS
KW - Chédiak-Higashi syndrome
KW - LYST
KW - SNP-array
KW - hemophagocytic lymphohistiocytosis
KW - loss of heterozygosity
KW - primary immunodeficiency
KW - uniparental disomy
KW - Severity of Illness Index
KW - Genetic Predisposition to Disease
KW - Humans
KW - Chediak-Higashi Syndrome/diagnosis
KW - Child, Preschool
KW - Uniparental Disomy
KW - Heredity
KW - Loss of Heterozygosity
KW - Mothers
KW - Homozygote
KW - Molecular Diagnostic Techniques
KW - Phenotype
KW - Pedigree
KW - Female
KW - Mutation
KW - Vesicular Transport Proteins/genetics
UR - http://www.scopus.com/inward/record.url?scp=85104207235&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.625591
DO - 10.3389/fimmu.2021.625591
M3 - Article
C2 - 33868243
AN - SCOPUS:85104207235
SN - 1664-3224
VL - 12
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 625591
ER -