Genetics of Combined Pituitary Hormone Deficiency: Roadmap into the Genome Era

Abstract

The genetic basis for combined pituitary hormone deficiency (CPHD) is complex, involving 30 genes in a variety of syndromic and nonsyndromic presentations. Molecular diagnosis of this disorder is valuable for predicting disease progression, avoiding unnecessary surgery, and family planning. We expect that the application of high throughput sequencing will uncover additional contributing genes and eventually become a valuable tool for molecular diagnosis. For example, in the last 3 years, six new genes have been implicated in CPHD using whole-exome sequencing. In this review, we present a historical perspective on gene discovery for CPHD and predict approaches that may facilitate future gene identification projects conducted by clinicians and basic scientists. Guidelines for systematic reporting of genetic variants and assigning causality are emerging. We apply these guidelines retrospectively to reports of the genetic basis of CPHD and summarize modes of inheritance and penetrance for each of the known genes. In recent years, there have been great improvements in databases of genetic information for diverse populations. Some issues remain that make molecular diagnosis challenging in some cases. These include the inherent genetic complexity of this disorder, technical challenges like uneven coverage, differing results from variant calling and interpretation pipelines, the number of tolerated genetic alterations, and imperfect methods for predicting pathogenicity. We discuss approaches for future research in the genetics of CPHD.

Figure 1.

Genetics of CPHD: timeline for discovery, cases explained, and developmental expression. A, Mouse pituitary development. Tissue fated to become Rathke's pouch is located at the anterior portion of the embryo. It is in constant contact with the neural ectoderm, which becomes the infundibulum. At e9.5, the oral ectoderm begins to invaginate to produce Rathke's pouch (horizontal hatching). At e12, the cartilage (black) begins to form, and Rathke's pouch pinches off. The posterior lobe (vertical hatching) is formed from evagination of neural ectoderm, and it produces FGF, which stimulates the growth of the pouch. The anterior and intermediate lobes are derived from Rathke's pouch and contain the major hormone-producing cell types by birth. The corresponding time in human development is weeks 4–9 (Carnegie stages 8–22) (418). Orientation: sagittal section with rostral to the left and dorsal at the top. I, infundibulum; H, heart; N, notochord; OM, oral membrane; PP, prechordal plate; F, forebrain; MB, midbrain; HB, hindbrain; AN, anterior neural pore; RP, Rathke's pouch; O, oral cavity; PL, posterior lobe; P, pontine flexure; OC, optic chiasma; IL, intermediate lobe; AL, anterior lobe; DI, diencephalon; PO, pons; SC, sphenoid cartilage. [Redrawn from H. Z. Sheng and H. Westphal: Early steps in pituitary organogenesis. Trends Genet. 1999;15(6):236–240 (166), with permission. © Elsevier.] B, The timeline of gene discovery for CPHD. The light gray bars represent the total number of genes identified by the candidate screening methods; the dark gray bars represent the total number of genes identified by the WES. For each year, the identified gene names are at the top of the bar. *, Gene identified by WES. C, Pie chart indicating the familial and sporadic cases of CPHD that were explained by mutations in the genes PROP1, POU1F1, LHX3, LHX4, and HESX1. Data are summarized from an extensive literature survey, which illustrates the variation in frequency of PROP1 mutations by ethnic groups (46). Because systematic screening has not yet been done for the other CPHD genes, it is not possible to estimate their frequency, but it is expected to be quite small.

Figure 2.

Work flow for assessment on the reported genetic variants of CPHD. A, Loss-of-function (LoF) variants; B, missense or in-frame insertion and deletion (in/del) variants.

Figure 3.

Examples of pathogenic variants identified in CPHD genes.

Figure 3.

Examples of pathogenic variants identified in CPHD genes.

Figure 4.

Molecular inversion probe (MIP) capture. A, MIP probe panels are synthesized in parallel on a microarray. B, In a single-well reaction, hundreds to thousands of exons are targeted in parallel by capture probes. As each probe anneals, the target is enzymatically copied and ligated to the probe backbone to yield a sequencing library. C, Example of MIPS sequencing data at GHRHR showing coverage for two samples, including a heterozygous missense SNV.