Piebaldism and Familial Gastrointestinal Stromal Tumors (GISTs) via the KIT Gene

Piebaldism is caused by inactivating pathogenic variants in KIT, while neoplasms (GISTs, GCTs, AML, CML and lymphomas) are caused by activating, or gain-of-function, pathogenic variants (Akin and Metcalf 2004). KIT encodes a transmembrane receptor tyrosine kinase that responds to the Stem Cell Factor (SCF) ligand. Kit is expressed on the surface of several different cell types, including melanocytes, gastrointestinal pacemaker cells, hematopoietic progenitor cells, mast cells and germ cells. In melanocytes, Kit signaling is required for migration from the embryonic neural crest; loss of Kit function results in the absence of melanocytes in midline patches of hair and skin. In other cells, signaling through the SCF/c-kit pathway promotes proliferation and survival; constitutive activation of Kit in these cells causes excessive proliferation, malignancy and metastasis. Loss-of-function variants are found throughout all 21 exons of the KIT gene, whereas activating variants appear to be clustered in exons 2, 8, 9, 11, 13 and 17 (Heinrich et al. 2002). Importantly, the selective Kit inhibitor Gleevec (Novartis Pharmaceuticals, East Hanover, NJ) is a very effective treatment for KIT-dependent neoplasms (Tuveson et al. 2001). However, a few activating variants, such as D816V, have been shown to be insensitive to Gleevec (Miettinen et al. 2002). As a result, identifying the causative variant in these neoplasms is critical for determining the most effective mode of treatment.

Pathogenic variants in the c-kit proto-oncogene (KIT) cause a variety of disorders, including piebaldism, gastrointestinal stromal tumors (GISTs), germ cell tumors (GCTs) and hematopoietic neoplasms such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and malignant lymphoma (Akin and Metcalfe 2004). Piebaldism is an autosomal dominant disorder characterized by patches of skin and hair that entirely lack pigment (Murakami et al. 2004). These white patches are mainly found on the scalp and forehead, resulting in a distinctive white forelock trait. Gastrointestinal stromal tumors, or GISTs, are rare mesenchymal tumors that specifically express the Kit protein and originate in the gastrointestinal (GI) tract or abdomen (Miettinen et al. 2002). In most cases, GISTs spontaneously arise due to somatic pathogenic variants of the KIT gene. However, families with germline pathogenic variants in the KIT gene have also been described (Isozaki et al. 2000; Maeyama et al. 2001). In these families, inheritance of heterozygous KIT variants leads to cutaneous hyperpigmentation and development of multiple GISTs.

This test is predicted to detect a loss-of-function pathogenic variant in nearly all patients with piebaldism (Syrris et al. 2002). The clinical sensitivity of germline pathogenic variants in KIT from individuals with GIST is considered to be low, but at least 16 variants have been reported in several families with multiple occurrences of GIST (Bachet et al. 2013).

The clinical sensitivity for detection of large deletions and duplications is not known; however, gross deletions have been reported for Piebaldism (Ezoe et al. 1995).

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