Case Report: Partial Uniparental Disomy Unmasks a Novel Recessive Mutation in the LYST Gene in a Patient With a Severe Phenotype of Chédiak-Higashi Syndrome

Abstract

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.

Chediak-Higashi syndrome

“…Nonetheless, mutations seem to be scattered all throughout the gene and are a combination of point/missense mutations, insertion/deletion, or frameshift variants [1,3,5,7,23,28 ▪ ,29,30,31 ▪ ,32–46]. A few reports identify canonical splice-site mutations and association with uniparental isodisomy [47,48].…”

From Mendel to mycoses: Immuno‐genomic warfare at the human–fungus interface

“…Severe Combined ImmunoDeficiency (SCID) CD45 311 Combined ImmunoDeficiency (CID) LCK 312 Severe Combined ImmunoDeficiency (SCID) ADA 313 CARD9 deficiency CARD9 290 IRF4 deficiency IRF4 314 LRBA deficiency LRBA 315 Activated PI3K-Delta Syndrome 1 PIK3CD 316 Chédiak-Higashi Syndrome LYST 317 Schimke immuno-osseous dysplasia SMARCAL1 318 Wiskott-Aldrich syndrome WAS 319 CNV X-linked agammaglobulinemia with neurologic impairment and sensorineural deafness BTK 320 Atypical SCID IL7R 321,322 Very early onset-inflammatory bowel disease (VEO-IBD) XIAP 323 Ataxia-telangiectasia ATM 324 Mendelian susceptibility to mycobacterial disease (MSMD) IFNGR1 325 Severe Combined ImmunoDeficiency (SCID) DCLRE1C 326 Williams-Beuren syndrome and Chronic Granulomatous Disease (CGD) NCF1 327 DOCK8 deficiency DOCK8 328 CTLA-4 deficiency CTLA4 329 Allelic imbalance Combined immunodeficiency (Artemis CID) DCLRE1C 330 CARD9 deficiency CARD9 31 Skewed X lyonization Wiskott-Aldrich syndrome WAS 319,[331][332][333][334][335][336][337][338] X-linked hyper-IgM CD40LG 339 Chronic Granulomatous Diseases CYBB [340][341][342] Mosaicism Germline mosaicism X-linked SCID IL2RG [343][344][345] Wiskott-Aldrich syndrome WAS 346 Several disorders…”

cDNA sequencing increases the molecular diagnostic yield in Chediak-Higashi syndrome

“…Conventional molecular genetic testing of LYST by Sanger sequencing of genomic DNA (gDNA) detects the majority of pathogenic variants, but for some individuals clinically diagnosed with CHS, pathogenic variants remain undetected, likely due to large-scale indels and deep intronic variants or synonymous exonic variants that lead to aberrant splicing. Uniparental disomy leading to the inheritance of two copies of a pathogenic LYST variant from one parent has also been reported as a molecular mechanism for CHS ( Dufourcq-Lagelouse et al, 1999 ; Manoli et al, 2010 ; Boluda-Navarro et al, 2021 ).…”

“…In this study, we aimed to provide a complete molecular diagnosis for six individuals with CHS by utilizing both conventional gDNA Sanger sequencing and cDNA Sanger sequencing. cDNA Sanger sequencing was chosen as a complementary method of variant detection since patient LYST -expressing dermal fibroblasts were available and because this method has been shown to effectively detect variant alleles that may not be readily detectable by conventional gDNA Sanger sequencing ( Certain et al, 2000 ; Boluda-Navarro et al, 2021 ). We hypothesize that this strategy will aid in the identification of variants in this technically challenging gene to better molecularly diagnose individuals with CHS in the future.…”

“…Several strategies have been used to sequence LYST. These strategies include conventional gDNA Sanger sequencing (Toro et al, 2009), cDNA Sanger sequencing (Boluda-Navarro et al, 2021), the protein truncation test followed by cDNA sequencing to screen for nonsense and frameshift variants and to identify substitutions and small indels in LYST (Certain et al, 2000), as well as next-generation sequencing approaches such as exome sequencing and genome sequencing, particularly if other candidate loci are being considered as part of the differential diagnosis (Jin et al, 2017).…”