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Title: Bi-allelic SMO variants in hypothalamic hamartoma: a recessive cause of Pallister-Hall syndrome.
Austin Authors: Green, Timothy E;Schimmel, Mareike;Schubert, Susanna;Lemke, Johannes R;Bennett, Mark F ;Hildebrand, Michael S ;Berkovic, Samuel F 
Affiliation: Epilepsy Research Centre
Department of Medical Biology, University of Melbourne, Melbourne, Vic, Australia
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Vic, Australia
Neuroscience Research Group, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Vic, Australia
Children's Hospital, University Hospital Augsburg, Augsburg, Germany
Institute of Human Genetics, University of Leipzig Medical Centre, Leipzig, Germany
Issue Date: Mar-2022
Date: 2022-01-16
Publication information: European Journal of Human Genetics 2022; 30(3): 384-388
Abstract: Pallister-Hall syndrome, typically caused by germline or de novo variants within the GLI3 gene, has key features of hypothalamic hamartoma and polydactyly. Recently, a few similar cases have been described with bi-allelic SMO variants. We describe two siblings born to non-consanguineous unaffected parents presenting with hypothalamic hamartoma, post-axial polydactyly, microcephaly amongst other developmental anomalies. Previous clinical diagnostic exome analysis had excluded a pathogenic variant in GLI3. We performed exome sequencing re-analysis and identified bi-allelic SMO variants including a missense and synonymous variant in both affected siblings. We functionally characterised this synonymous variant showing it induces exon 8 skipping within the SMO transcript. Our results confirm bi-allelic SMO variants as an uncommon cause of Pallister-Hall syndrome and describe a novel exon-skipping mechanism, expanding the molecular architecture of this new clinico-molecular disorder.
DOI: 10.1038/s41431-021-01023-4
ORCID: 0000-0002-4435-6610
Journal: European Journal of Human Genetics : EJHG
PubMed URL: 35034092
PubMed URL:
Type: Journal Article
Appears in Collections:Journal articles

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