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Potential hot spot for de novo mutations in PTCH1 gene in Gorlin syndrome patients: a case report of twins from Croatia.

ABSTRACT: We describe a case of twins with sporadic Gorlin syndrome. Both twins had common Gorlin syndrome features including calcification of the falx cerebri, multiple jaw keratocysts, and multiple basal cell carcinomas, but with different expressivity. One brother also had benign testicular mesothelioma. We propose this tumor type as a possible new feature of Gorlin syndrome. Gorlin syndrome is a rare autosomal dominant disorder characterized by both developmental abnormalities and cancer predisposition, with variable expression of various developmental abnormalities and different types of tumors. The syndrome is primarily caused by mutations in the Patched 1 (PTCH1) gene, although rare mutations of Patched 2 (PTCH2) or Suppressor of Fused (SUFU) genes have also been found. Neither founder mutations nor hot spot locations have been described for PTCH1 in Gorlin syndrome patients. Although de novo mutations of the PTCH1 gene occur in almost 50% of Gorlin syndrome cases, there are a few recurrent mutations. Our twin patients were carriers of a de novo mutation in the PTCH1 gene, c.3364_3365delAT (p.Met1122ValfsX22). This is, to our knowledge, the first Gorlin syndrome-causing mutation that has been reported four independent times in distant geographical locations. Therefore, we propose the location of the described mutation as a potential hot spot for mutations in PTCH1.

SUBMITTER: Musani V

PROVIDER: S-EPMC5833102 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Potential hot spot for de novo mutations in PTCH1 gene in Gorlin syndrome patients: a case report of twins from Croatia.

Musani Vesna V Ozretić Petar P Trnski Diana D Sabol Maja M Poduje Sanja S Tošić Mateja M Šitum Mirna M Levanat Sonja S

Croatian medical journal 20180201 1

We describe a case of twins with sporadic Gorlin syndrome. Both twins had common Gorlin syndrome features including calcification of the falx cerebri, multiple jaw keratocysts, and multiple basal cell carcinomas, but with different expressivity. One brother also had benign testicular mesothelioma. We propose this tumor type as a possible new feature of Gorlin syndrome. Gorlin syndrome is a rare autosomal dominant disorder characterized by both developmental abnormalities and cancer predispositio ...[more]

PMID: 29498494

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Project description:Gorlin syndrome or nevoid basal cell carcinoma syndrome is a rare genetic disease characterized by predisposition to congenital defects, basal cell carcinomas and medulloblastoma. The syndrome results from a heritable mutation in PATCHED1 (PTCH1), causing constitutive activation of the Hedgehog pathway. The present study described a patient with Gorlin syndrome who presented early in life with characteristic basal cell carcinomas and later developed a small cell glioblastoma (GBM), World Health Organization grade IV, associated with a Patched 1 (PTCH1) N97fs*43 mutation. Comprehensive genomic profiling of GBM tissues also revealed multiple co-occurring alterations including cyclin-dependent kinase 4 (CDK4) amplification, receptor tyrosine-protein kinase 3 (ERBB3) amplification, a fibroblast growth factor receptor 1 and transforming acidic coiled-coil containing protein 1 (FGFR1-TACC1) fusion, zinc finger protein (GLI1) amplification, E3 ubiquitin-protein ligase (MDM2) amplification and spectrin α chain, erythrocytic 1 (SPTA1) T1151fs*24. After the biopsy, imaging revealed extensive leptomeningeal enhancement intracranially and around the cervical spinal cord due to leptomeningeal disease. The patient underwent craniospinal radiation followed by 6 months of adjuvant temozolomide (150 mg/m2) with good response. She was then treated with vismodegib for 11 months, first combined with temozolomide and then with bevacizumab, until disease progression was noted on MRI, with no significant toxicities associated with the combination therapy. She received additional therapies but ultimately succumbed to the disease four months later. The current study presents the first documentation in the literature of a primary (non-radiation induced) glioblastoma secondary to Gorlin syndrome. Based on this clinical experience, vismodegib should be considered in combination with standard-of-care therapies for patients with known Gorlin syndrome-associated glioblastomas and sonic hedgehog pathway mutations.

Project description:Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 × 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p.Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 × 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.

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Potential hot spot for de novo mutations in PTCH1 gene in Gorlin syndrome patients: a case report of twins from Croatia.

Publications

Potential hot spot for de novo mutations in PTCH1 gene in Gorlin syndrome patients: a case report of twins from Croatia.

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