Chediak-Higashi Syndrome (CHS) via the LYST Gene

Chediak-Higashi syndrome (CHS) (OMIM 214500) is characterized by partial albinism, bleeding diathesis, nystagmus, neutropenia, and other immunodeficiencies causing recurrent infections (Chediak. Rev Hematol 7:362-367, 1952; Higashi Tohoku. J Exp Med 59:315-332, 1954; Donohue and Bain. Pediatrics 20:416-430, 1957). Bleeding diathesis results from deficient platelet-dense granules that, in unaffected individuals, normally harbor signaling molecules essential for thrombosis. The CHS phenotype is similar to that of Hermansky Pudlak syndrome (HPS) (OMIM 203300), and both diseases are related to storage granule abnormalities. Blood smears and biopsies from CHS patients show giant inclusion bodies in granulocytes and cells from other tissues including skin and muscle (Introne et al. Mol Genet Metab 68:283-303, 1999). Most patients present symptoms in early childhood. Rarely, a patient may exhibit an intermediate adolescent CHS phenotype. In all forms of CHS, patients develop neurologic deficiencies including decreased cognitive ability, balance abnormalities, tremors, and other motor and sensory neuropathies (Tardieu et al. Blood 106:40-42, 2005). Approximately 85% of patients develop an accelerated phase of the disease known as hemophagocytic lymphohistiocytosis and characterized by hepatosplenomegaly, fever, jaundice, pancytopenia, and attenuated NK cell function (Blume and Wolff. Medicine (Baltimore) 51:247-280, 1972; Henter et al. Pediatr Blood Cancer 48:124-131, 2007).

Chediak-Higashi syndrome (CHS) is an autosomal recessive disorder associated with the LYST gene (OMIM 606897). The exact function of the LYST protein is unknown, however LYST interacts with SNARE proteins, which are key members of the intracellular membrane fusion apparatus in cells. LYST may function as an adapter protein that helps juxtapose fusing membranes (Tchernev. Mol Med 8:56-64, 2002). Variants in LYST account for ~70% of CHS cases. Approximately 50 causative variants have been identified throughout the LYST gene including missense and nonsense variants, and small insertions and deletions. Studies show that patients with severe childhood CHS typically have functionally null mutant LYST alleles. In contrast, patients with adolescent and adult forms of CHS typically harbor missense variants resulting in LYST polypeptides that likely retain some functionality (Karim et al. Am J Med Genet 108:16-22, 2002; Westbroek et al. J Invest Dermatol 127:2674-2677, 2007; Zarzour. Mol Genet Metab 85:125-132, 2005).

Causative variants in the LYST gene have been found in ~ 70% of CHS cases.

This test provides full coverage of all coding exons of the LYST gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.