A Hypomorphic Allele in the FGF8 Gene Contributes to Holoprosencephaly and Is Allelic to Gonadotropin-Releasing Hormone Deficiency in Humans

Abstract

Holoprosencephaly (HPE), the most common malformation of the human forebrain, may arise due to interacting genetic and environmental factors. To date, at least 12 contributory genes have been identified. Fibroblast growth factor 8 (Fgf8) belongs to the FGF family of genes expressed in several developmental signaling centers, including the anterior neural ridge, which is implicated in midline anomalies in mice. In humans, FGF8 mutations have been previously reported in facial clefting and in hypogonadotropic hypogonadism, but have not been reported in patients with HPE. We screened 360 probands with HPE for sequence variations in FGF8 using High Resolution DNA Melting (HRM) and sequenced all identified variations. Here we describe a total of 8 sequence variations in HPE patients, including a putative loss-of-function mutation in 3 members of a family with variable forms of classic HPE, and relate these findings to the phenotypes seen in other conditions.

Fig. 1

HRM detection of variant c.686C>T, resulting in p.T229M in exon 6 of FGF8. a Temperature melt profile of the variant (in magenta) is distinct from wild types. b Differential plot illustrates the variant (in magenta) is distinct from wild types. c Representative chromatogram shows the DNA sequence variation detected in all 3 members of the family.

Fig. 2

Pedigree of family segregating FGF8 mutation. As the legend indicates, individuals with the right side shaded blue segregate the c.686C>T mutation in FGF8. Individuals I.1 and II.2 display microform features, indicated by yellow shading, while patient II.1 had semilobar HPE, indicated by black shading. Individuals II.3 and II.4 were not tested, but by history and photo review had no findings consistent with microform HPE or other related issues.