Bamforth-Lazarus Syndrome via the FOXE1 Gene

Bamforth-Lazarus syndrome is a congenital genetic disorder characterized by hypothyroidism due to thyroid dysgenesis, cleft palate and spiky hair. Some patients with this disease also present with bifid epiglottis and choanal atresia (Bamforth et al. 1989; Clifton-Bligh et al. 1998; Castanet et al. 2002; Baris et al. 2006). In an isolated case, porencephaly has also been reported (Sandal et al. 2013). Bamforth-Lazarus syndrome is very rare with a prevalence of < 1/1,000,000 (www.orpha.net).

Bamforth-Lazarus syndrome is inherited in an autosomal recessive manner. Homozygous pathogenic variants in FOXE1 have been reported in several patients born from consanguineous marriages (Bamforth et al. 1989; Castanet et al. 2002; Baris et al. 2006). FOXE1 belongs to a family of forkhead box (FOX) transcription factors with a conserved winged-helix DNA-binding domain (Romanelli et al. 2003). Except for a gross deletion, all the reported pathogenic variants to date are missense and are clustered within the FOX domain (Human Gene Mutation Database), which is essential for gene transcription. FOXE1 regulates the expression of thyroglobulin (TG) and thyroid peroxidase (TPO) and plays important roles in the maintenance of thyroid function, including the production and secretion of thyroid hormones (Cuesta et al. 2007).

A heterozygous variant (p. Ala248Gly) in the FOXE1 gene has also been observed in a family with non-medullary thyroid carcinoma (FNMTC) (Pereira et al. 2015).

It is difficult to estimate the clinical sensitivity of this test due to the lack of large cohort studies. Almost all the pathogenic variants reported to date in FOXE1 gene are detectable by sequencing.

It is difficult to estimate the clinical sensitivity of this test due to the lack of large cohort studies. To date, only one gross deletion has been identified involving FOXE1 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the FOXE1 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).