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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.
Highlights
Uniparental disomy (UPD) is an unusual genetic mechanism in which homologous copies of a specific chromosome are inherited from only one parent [1]
This study reports the first case of Chédiak-Higashi syndrome (CHS) as a result of partialUPiD
72 mutations in this gene have been associated with CHS [20], and UPD has been reported as the causative mechanism only in three CHS cases [17, 21]
Summary
Uniparental disomy (UPD) is an unusual genetic mechanism in which homologous copies of a specific chromosome are inherited from only one parent [1]. Even though the exact function of the LYST protein is still debated, the combined PH-BEACH motifs are thought to be implicated in different aspects of vesicular trafficking and, likely playing a crucial role in regulating lysosome-related organelle size, fission and secretion [12,13,14] Both homozygous and compound heterozygous mutations in LYST gene have been previously described in CHS [10]. Due to the clinical phenotype that included albinism, together with the defective degranulation assay and the presence of cytoplasmic lysosomal vesicles in granulocytic cells, we amplified by PCR the entire patient’s cDNA sequence of LYST gene (53 exons) in 5 overlapping fragments (Supplementary Table 2, Supplementary Figure 1A). After 2 years since the transplant, the patient maintains complete donor chimerism, showing a normal physical and neurological development, and has not required subsequent admissions into the hospital
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