Novel<i> SUFU</i> Frameshift Variant Leading to Meningioma in Three Generations in a Family with Gorlin Syndrome

Askaner, Gustav; Lei, Ulrikke; Bertelsen, Birgitte; Venzo, Alessandro; Wadt, Karin

doi:10.1155/2019/9650184

Cited by 10 publications

(14 citation statements)

References 17 publications

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“…Localization of SUFU variants associated in previous studies with Joubert syndrome are indicated in green and blue; variants associated with Gorlin–Goltz syndrome are marked in red. 19 , 22 , 27 , 28 . …”

Section: Resultsmentioning

confidence: 99%

Heterozygous truncating variants in SUFU cause congenital ocular motor apraxia

Schröder

Yiğit

et al. 2021

Genetics in Medicine

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Purpose This study aimed to delineate the genetic basis of congenital ocular motor apraxia (COMA) in patients not otherwise classifiable. Methods We compiled clinical and neuroimaging data of individuals from six unrelated families with distinct clinical features of COMA who do not share common diagnostic characteristics of Joubert syndrome or other known genetic conditions associated with COMA. We used exome sequencing to identify pathogenic variants and functional studies in patient-derived fibroblasts. Results In 15 individuals, we detected familial as well as de novo heterozygous truncating causative variants in the Suppressor of Fused (SUFU) gene, a negative regulator of the Hedgehog (HH) signaling pathway. Functional studies showed no differences in cilia occurrence, morphology, or localization of ciliary proteins, such as smoothened. However, analysis of expression of HH signaling target genes detected a significant increase in the general signaling activity in COMA patient–derived fibroblasts compared with control cells. We observed higher basal HH signaling activity resulting in increased basal expression levels of GLI1, GLI2, GLI3, and Patched1. Neuroimaging revealed subtle cerebellar changes, but no full-blown molar tooth sign. Conclusion Taken together, our data imply that the clinical phenotype associated with heterozygous truncating germline variants in SUFU is a forme fruste of Joubert syndrome.

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Section: Resultsmentioning

confidence: 99%

Heterozygous truncating variants in SUFU cause congenital ocular motor apraxia

Schröder

Yiğit

et al. 2021

Genetics in Medicine

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“…The risk of BCC in adult patients with germline SUFU mutations has not been estimated yet. Several SUFU PV carriers identified in GS cohorts have been diagnosed with multiple BCC [12][13][14][15], but most SUFU PVs were identified in infants treated for a medulloblastoma who were young at the time of clinical report and therefore their risk of BCC in adulthood cannot be assessed. In their relatives, the risk of BCC in adults is much lower than in classical GS related to PTCH1 PVs [6] suggesting that the risk of BCC in SUFU PV carriers is much lower than in PTCH1 PV carriers.…”

Section: Basal Cell Carcinoma (Bcc)mentioning

confidence: 99%

“…Indeed, in the Manchester cohort, the incidence of meningiomas was much higher in SUFU PV carriers (4/9) than in patients with a PTCH1 PV (2/126). Meningiomas have also been described, mostly as case reports, in patients with SUFU variants, either as the first brain tumor [ 12 , 14 , 25 ] or, more frequently, after irradiation for a medulloblastoma [ 6 , 13 , 26 , 27 ]. Most de novo meningiomas described so far occurred after the age of 40, whereas they occurred earlier in patients previously treated for a medulloblastoma.…”

Section: Genetic Associationsmentioning

confidence: 99%

“…Most de novo meningiomas described so far occurred after the age of 40, whereas they occurred earlier in patients previously treated for a medulloblastoma. In addition, two multigenerational families with meningiomas as the major feature in multiple affected family members have been associated with an inherited germline SUFU variant [ 12 , 25 ].…”

Section: Genetic Associationsmentioning

confidence: 99%

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Current recommendations for cancer surveillance in Gorlin syndrome: a report from the SIOPE host genome working group (SIOPE HGWG)

et al. 2021

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Gorlin syndrome (MIM 109,400), a cancer predisposition syndrome related to a constitutional pathogenic variation (PV) of a gene in the Sonic Hedgehog pathway (PTCH1 or SUFU), is associated with a broad spectrum of benign and malignant tumors. Basal cell carcinomas (BCC), odontogenic keratocysts and medulloblastomas are the main tumor types encountered, but meningiomas, ovarian or cardiac fibromas and sarcomas have also been described. The clinical features and tumor risks are different depending on the causative gene. Due to the rarity of this condition, there is little data on phenotype-genotype correlations. This report summarizes genotype-based recommendations for screening patients with PTCH1 and SUFU-related Gorlin syndrome, discussed during a workshop of the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) held in January 2020. In order to allow early detection of BCC, dermatologic examination should start at age 10 in PTCH1, and at age 20 in SUFU PV carriers. Odontogenic keratocyst screening, based on odontologic examination, should begin at age 2 with annual orthopantogram beginning around age 8 for PTCH1 PV carriers only. For medulloblastomas, repeated brain MRI from birth to 5 years should be proposed for SUFU PV carriers only. Brain MRI for meningiomas and pelvic ultrasound for ovarian fibromas should be offered to both PTCH1 and SUFU PV carriers. Follow-up of patients treated with radiotherapy should be prolonged and thorough because of the risk of secondary malignancies. Prospective evaluation of evidence of the effectiveness of these surveillance recommendations is required.

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“…From our experience, a clear distinction between a definite molar tooth sign and a milder hindbrain malformation as described here is occasionally challenging, even with a technically optimal MRI investigation. 19,22,27,28 .…”

Section: Discussionmentioning

confidence: 99%