Complex mode of inheritance in holoprosencephaly revealed by whole exome sequencing

Abstract

Holoprosencephaly (HPE) is the most common congenital cerebral malformation, characterized by impaired forebrain cleavage and midline facial anomalies. Heterozygous mutations in 14 genes have been associated with HPE and are often inherited from an unaffected parent, underlying complex genetic bases. It is now emerging that HPE may result from a combination of multiple genetic events, rather than from a single heterozygous mutation. To explore this hypothesis, we undertook whole exome sequencing and targeted high-throughput sequencing approaches to identify mutations in HPE subjects. Here, we report two HPE families in which two mutations are implicated in the disease. In the first family presenting two foetuses with alobar and semi-lobar HPE, we found mutations in two genes involved in HPE, SHH and DISP1, inherited respectively from the father and the mother. The second reported case is a family with a 9-year-old girl presenting lobar HPE, harbouring two compound heterozygous mutations in DISP1. Together, these cases of digenic inheritance and autosomal recessive HPE suggest that in some families, several genetic events are necessary to cause HPE. This study highlights the complexity of HPE inheritance and has to be taken into account by clinicians to improve HPE genetic counselling.

Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway

“…These cases of double mutations in two different genes—and even in the same one—strengthen the polygenic inheritance previously illustrated by Mouden et al. (). Here, a second event in FGF8 was identified in one patient with FGFR1 mutation.…”

“…Thanks to our NGS strategy targeting 20 genes, we have shown that 16% of mutations kept for diagnosis was found in association with a second one (FGF8/FGFR1, FGF8/DLL1, DLL1/SHH, DISP1/DISP1, DISP1/SUFU). These cases of double mutations in two different genes-and even in the same one-strengthen the polygenic inheritance previously illustrated by Mouden et al (2016). Here, a second event in FGF8 was identified in one patient with FGFR1 mutation.…”

“…Furthermore, the description of numerous mouse models carrying mutations in two genes of the same or different signaling pathways involved in forebrain development strongly support this mode of inheritance by showing that a cumulative partial inhibition of signaling pathways is necessary to develop HPE [Allen et al., ; Krauss, ; Mercier et al., ]. However, only a few examples of digenic inheritance in human were reported in the literature until now [Nanni et al., ; Ming and Muenke, ; Lacbawan et al., ; Hong et al., ; Mouden et al., ]. The present study demonstrates that digenism would not be so rare in human HPE.…”

Common genetic causes of holoprosencephaly are limited to a small set of evolutionarily conserved driver genes of midline development coordinated by TGF-β, hedgehog, and FGF signaling

“…Variants were not filtered for allele frequency. However, variants detected at frequencies above the incidence of holoprosencephaly among newborns are given an asterix (* We selected a list of candidate genes that surveyed major steps in hedgehog signal transduction, ligand and receptor processing, target genes described in the published literature (Vokes et al, 2007) and reviews, as well as proposed candidate genes from other investigators Mouden et al, 2015Mouden et al, , 2016 or proponents of a link between hedgehog signaling and the cilium (Garcia- Gonzalo et al, 2015;Goetz & Anderson, 2010;Liem et al, 2012) or cholesterol metabolism (Haas & Muenke, 2010). In order to study the potential of gene-gene interactions and/or additional developmental pathways, we included the human versions of prominent ligands and receptors of the fgf, bmp, notch, tgf , and wnt pathways and key enzymes for cholesterol synthesis for a total of 153 individual genes (see Supporting Information Table S4, column AI).…”

Heterozygous mutation of Sonic Hedgehog receptor (Ptch) drives cerebellar overgrowth and sex-specifically alters hippocampal and cortical layer structure, activity, and social behavior in female mice

“…In humans, ADHD has been associated with HPE caused by SHH mutations primarily in female humans with noted high intellectual function (Heussler et al, 2002; Solomon et al, 2012), demonstrating that altered SHH signaling can lead to hyperactivity. Similar to the sex differences observed in Ptch1 +/- female mice, human females are also at increased risk for diagnosis of HPE with sex ratios ranging from 1.2:1 to 2.3:1 female:male (Croen et al, 1996; Mouden et al, 2016; Weiss et al, 2018a). The prosocial phenotype observed in Ptch1 +/- females may be due to a mild sex-specific HPE-like hyperactive phenotype resulting in indiscriminate social interactions.…”