Bi-allelic SMO variants in hypothalamic hamartoma: a recessive cause of Pallister-Hall syndrome.

Timothy E Green, Mareike Schimmel, Susanna Schubert, Johannes R Lemke, Mark F Bennett, Michael S Hildebrand, Samuel F Berkovic

European journal of human genetics : EJHG 2022 Mar

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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. © 2021. The Author(s), under exclusive licence to European Society of Human Genetics.

Citation

Timothy E Green, Mareike Schimmel, Susanna Schubert, Johannes R Lemke, Mark F Bennett, Michael S Hildebrand, Samuel F Berkovic. Bi-allelic SMO variants in hypothalamic hamartoma: a recessive cause of Pallister-Hall syndrome. European journal of human genetics : EJHG. 2022 Mar;30(3):384-388