Histiocytosis-Lymphadenopathy Plus Syndrome via the SLC29A3 Gene

Histocytosis-Lymphadenopathy Plus syndrome, also known as SLC29A3 spectrum disorder, comprises four disorders that were initially thought to be distinct entities, but in fact show extensive phenotypic overlap. The four disorders include Faisalabad histiocytosis (FHC), H syndrome, sinus histiocytosis with massive lymphadenopathy (aka familial Rosai-Dorfman disease), and pigmented hypertrichosis and insulin-dependent diabetes (PHID). Histiocytosis is characterized by an excessive number of histiocytes that phagocytose other cells and process antigens. While histiocytosis is a common feature among most patients with SLC29A3-related disorders, other features are variable among patients and include generalized lymphadenopathy, joint swelling, fever, leukocytosis, polyclonal hypergammaglobulinemia, hyperpigmentation, hypertrichosis, heart anomalies, hepatosplenomegaly, hypogonadism, hearing loss, and antibody-negative insulin-dependent diabetes mellitus (Morgan et al. 2010. PubMed ID: 20140240; Kismet et al. 2005. PubMed ID: 16118898; Cliffe et al. 2009. PubMed ID: 19336477; Bolze et al. 2012. PubMed ID: 22238637).

Pathogenic variants in the SLC29A3 (aka ENT3) gene are associated with rare syndromic forms of autosomal recessive familial histiocytosis. Other genes associated with familial histiocytosis disorders include PRF1, UNC13D, STX11, STXBP2, and the X-linked genes XIAP and SH2D1A. The SLC29A3 gene encodes a pH-dependent, nucleoside transporter (ENT3) that localizes to late endosome/lysosomal membranes and to mitochondria (Baldwin et al. 2005. PubMed ID: 15701636; Govindarajan et al. 2009. PubMed ID: 19164483). ENT3 is produced in many tissues including the placenta, uterus, ovary, spleen, lymph nodes, and nervous system. Pathogenic variants include missense variants and protein truncating variants such as splice site variants and small frameshift deletions and affect protein expression levels, localization, and transporter function (Molho-Pessach. 2008. PubMed ID: 18940313; Kang. 2010. PubMed ID: 20595384). Large deletions and duplications involving SLC29A3 have not been reported in patients. Two reported pathogenic variants, p.Gly427Ser and p.Gly437Arg, are found at frequencies of ~1% among Arab populations (Molho-Pessach. 2008. PubMed ID: 18940313).

SLC29A3 spectrum disorders are rare and are found primarily in patients of Arab descent. For example, fewer than 100 patients with H syndrome have been reported in the literature (Bloom et al. 2017. PubMed ID: 29041934).

This test provides full coverage of all coding exons of the SLC29A3 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).