Pallister-Hall syndrome, GLI3, and kidney malformation
Kathryn McClelland1, Weili Li2, Norman D Rosenblum1,3
1Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Insights
Pallister-Hall syndrome (PHS) is linked to congenital anomalies of the kidney and urinary tract (CAKUT) in 26.9% of patients. Specific GLI3 gene variants and other defects are associated with CAKUT in PHS.
Area of Science:
- Genetics
- Developmental Biology
- Medical Genetics
Background:
- Pallister-Hall syndrome (PHS) is a rare autosomal dominant disorder.
- It is characterized by hypothalamic hamartoma, mesoaxial polydactyly, and GLI3 gene truncating variants.
- PHS can manifest with diverse clinical phenotypes, including congenital anomalies of the kidney and urinary tract (CAKUT).
Purpose of the Study:
- To investigate the prevalence and characteristics of CAKUT in PHS patients.
- To identify clinical phenotypes associated with CAKUT in PHS.
- To explore the relationship between specific GLI3 variants and the occurrence of CAKUT in PHS.
Main Methods:
- Systematic analysis of reported PHS patient data (n=78).
- Review of clinical phenotypes, focusing on CAKUT presentation (hypoplasia, agenesis).
- Correlation analysis between CAKUT, other PHS features, and GLI3 variant types (substitution vs. deletion).
Main Results:
- CAKUT was present in 26.9% (21/78) of PHS patients, with hypoplasia/dysplasia and agenesis being common.
- CAKUT showed significant associations with craniofacial defects, bifid epiglottis, and disorders of sex development.
- PHS patients with CAKUT predominantly harbored substitution variants in the middle third of the GLI3 gene, unlike deletion variants in non-CAKUT patients.
Conclusions:
- Congenital anomalies of the kidney and urinary tract are a significant feature of Pallister-Hall syndrome.
- Specific GLI3 variant types may influence the development of CAKUT and associated phenotypes in PHS.
- Further research is needed to elucidate the molecular mechanisms underlying GLI3-mediated organogenesis defects in PHS.
Abstract:
Pallister-Hall syndrome (PHS) is a rare autosomal dominant disease diagnosed by the presence of hypothalamic hamartoma, mesoaxial polydactyly and a truncating variant in the middle third of the GLI-Kruppel family member 3 (GLI3) gene. PHS may also include a wide range of clinical phenotypes affecting multiple organ systems including congenital anomalies of the kidney and urinary tract (CAKUT). The observed clinical phenotypes are consistent with the essential role of GLI3, a transcriptional effector in the hedgehog (Hh) signaling pathway, in organogenesis. However, the mechanisms by which truncation of GLI3 in PHS results in such a variety of clinical phenotypes with variable severity, even within the same organ, remain unclear. In this study we focus on presentation of CAKUT in PHS. A systematic analysis of reported PHS patients (n = 78) revealed a prevalence of 26.9% (21/78) of CAKUT. Hypoplasia (± dysplasia) and agenesis were the two main types of CAKUT; bilateral and unilateral CAKUT were reported with equal frequency. Examination of clinical phenotypes with CAKUT revealed a significant association between CAKUT and craniofacial defects, bifid epiglottis and a Disorder of Sex Development, specifically affecting external genitalia. Lastly, we determined that PHS patients with CAKUT predominately had substitution type variants (as opposed to deletion type variants in non-CAKUT PHS patients) in the middle third of the GLI3 gene. These results provide a foundation for future work aimed at uncovering the molecular mechanisms by which variant GLI3 result in the wide range and severity of clinical features observed in PHS.
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