Analysis of genotype-phenotype correlations in human holoprosencephaly

Abstract

Since the discovery of the first gene causing holoprosencephaly (HPE), over 500 patients with mutations in genes associated with non-chromosomal, non-syndromic HPE have been described, with detailed descriptions available in over 300. Comprehensive clinical analysis of these individuals allows examination for the presence of genotype-phenotype correlations. These correlations allow a degree of differentiation between patients with mutations in different HPE-associated genes and for the application of functional studies to determine intragenic correlations. These early correlations are an important advance in the understanding of the clinical aspects of this disease, and in general argue for continued analysis of the genetic and clinical findings of large cohorts of patients with rare diseases in order to better inform both basic biological insight and care and counseling for affected patients and families.

Figure 1

Facial findings in patients with mutations in HPE-associated genes, showing the range of anomalies. Clockwise from top left, photos show: a patient with alobar HPE due to a deletion of TGIF, with synophthalmia and a proboscis [Münke et al., 1988; Roessler et al., 1996]; a patient with alobar HPE due to a mutation in SIX3 demonstrating hypotelorism, a flat nasal bridge, colobomata, and a facial cleft [Lacbawan et al., 2009]; a patient with lobar HPE due to a mutation in SIX3, demonstrating relatively mild but clear signs of HPE, including hypotelorism and a flat nasal bridge [Lacbawan et al., 2009]; a patient with microform HPE due to a mutation in SHH, who has a hypotelorism and a single central incisor [Roessler et al., 1996]. All images reprinted with permission Reproduced from: Roessler et al., Mutations in the human Sonic Hedgehog gene cause holoprosencephaly, 14:357, Copyright (1996), with permission from Nature Publishing Group; Lacbawan et al., Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function, 46:390, copyright notice 2009, with permission from BMJ Publishing Group, Ltd.

Figure 2

Proportion of HPE cases among all patients with mutations in the four classic HPE genes by the presence (dark bars) or absence of structural brain anomalies (SBA). Note the non-SBA group consists of individuals with mutations and either microform findings (grey bars) or who were apparently normal by standard clinical criteria yet also mutation positive (light bars). Note that the authors suspect that many individuals described as being clinically unaffected may have unappreciated microform features.

Figure 3

Distribution of mutations by HPE anatomical types among all individuals with clinically apparent penetrant findings (SBA or Microform patients with inclusion requiring (1) the presensce of mutation by sequencing and (2) clinical signs of HPE). (a) All affected mutation-positive individuals; (b) a subset including all propositi. The total number of patients in each group of vertical bars is presented in parentheses.