SUFU

Inheritance Pattern: AD

Disease ID:MONDO:0007187

Submitter: Illumina

The SUFU gene is located on chromosome 10 at 10q24.32 and encodes the suppressor of fused homolog protein, which is a negative regulator for the hedgehog/smoothened signaling pathway. The SUFU gene was first reported in relation to Gorlin syndrome (known as nevoid basal cell carcinoma syndrome) and atypical Gorlin syndrome, in 2009 (19533801; Pastorino et al. 2009). Evidence supporting this gene-disease relationship includes case-level data and experimental data. From a selection of literature, at least seven variants have been reported in a heterozygous state in eight affected individuals in six publications (19533801: Pastorino et al. 2009; 22829011: Kijima et al. 2012; 25403219: Smith et al. 2014; 29892665: Ogden et al. 2018; 29356994: Huq et al. 2018; 31485359: Askaner et al. 2019). The mechanism for disease is loss of function. Experimental evidence demonstrates that a splice donor variant was unable to interact with GLI transcription factors, resulting in activation of SHH pathway target genes (12068298: Taylor et al. 2002; 16459298: Svard et al. 2006). In a mouse model, in which mice were heterozygous for functional Sufu, a skin phenotype similar to Gorlin syndrome was observed (16459298: Svard et al. 2006). In summary, SUFU is definitively associated with autosomal dominant nevoid basal cell carcinoma syndrome.

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0018772

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0007187

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0018772

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0007187

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0033309

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

*SUFU* (OMIM: 607035) is located in chromosome region 10q24.32 and encodes for Suppressor of fused homolog, which inhibits the transcriptional activity of GLI1, GLI2, and GLI3 in response to SHH stimulation (PMID: 10559945, PMID: 10564661). *SUFU* has previously been curated by the Hereditary Cancer GCEP as Definitive for Medulloblastoma, autosomal-dominant (MONDO:0007959) (10/11/2018). *SUFU* is asserted to cause Joubert-Syndrome 32, autosomal-recessive (MONDO:0033309), and Ocular motor apraxia, Cogan type, autosomal-dominant (MONDO:0009764). Per the criteria outlined by the ClinGen Lumping and Splitting Working Group, these disease entities differ in mode of inheritance and are therefore split for this curation. Consistent with previous gene-disease curations by the Kidney Cystic and Ciliopathy Disorders GCEP, the Joubert-Syndrome 32, autosomal-recessive (MONDO:0033309) phenotype was curated under one disease entity, ciliopathy, autosomal-recessive inheritance (MONDO:0005308). Homozygous missense variants in SUFU were identified in four affected children with Joubert syndrome from two unrelated consanguineous families (PMID: 28965847). Affected individuals presented with mild features of Joubert syndrome, including cranio-facial anomalies and polydactyly (PMID: 28965847). Functional evidence in both patient-derived and transfection cell models for each missense variant (p.Ile406Thr and p.His176Arg) showed reduced SUFU stability and capacity to bind and cleave GLI3 into its repressor form (PMID: 28965847). In each case, biallelic missense variants cause altered protein function, consistent with a loss-of-function mechanism. The genetic evidence was scored at 1 total point (0.5 points for each proband). Mice with a homozygous *SUFU* missense variant (p.The396Ile) have reduced stability of the mutant SUFU protein, leading to dysregulated GLI3 activity, demonstrating embryonic lethality at E14–18 with peripheral edema, hemorrhage, and severe morphological defects including exencephaly and polydactyly (PMID: 25760946). The clinical and functional anomalies of this knock-in model closely resemble those of the affected children described in De Mori et al. 2017 (PMID: 28965847) (2 points for experimental evidence). The homozygous *Sufu* knockout mouse model developed by Svärd et al. demonstrated embryonic lethality at E9.5 and showed severe cranio-facial and neural closure defects related to constitutive sonic hedgehog (SHH) pathway activation and is consistent with a ciliopathy phenotype (PMID:16459298). Another mouse model with a conditional *Sufu* gene deletion in the mid-hindbrain demonstrates morphological defects of the brainstem and cerebellum with dysregulated HH signaling, and ablation of the GLI3-repressor activity (PMID: 21289193). SUFU is an essential negative regulator of the HH pathway through GLI transcription factor regulation (PMID: 10564661). SUFU binds to GLI1, GLI2, and GLI3 and inhibits their transcriptional activity in response to SHH signaling at the primary cilium (Protein interaction scored for 0.5 points). SUFU acts within the GLI-SUFU complex (GO:1990788) to repress GLI transcription factor activity when SMO signaling is inactive. Disruption to SHH signaling at the primary cilium, particularly to GLI3 activity, is associated with characteristic ciliopathy defects of the brain, cranio-facial, and limb development (Biochemical Function scored for 0.5 points). While outside of the scope of this gene curation, it is notable that *SUFU* is associated with a mild monoallelic phenotype, Ocular motor apraxia, Cogan type, autosomal-dominant (MONDO:0009764), observed in 37 affected children with heterozygous truncating variants in *SUFU* (PMID: 34675124, 33024317). It is suspected that these cases may constitute a mild dominant form of the autosomal-recessive ciliopathy phenotype (PMID: 34675124). Interestingly, congenital ocular motor apraxia and other characteristic features of Joubert syndrome have not been reported in patients with the *SUFU*-Medulloblastoma phenotype. However, due to the young age of these reported probands and our limited understanding of the *SUFU*-ciliopathy phenotype, these may represent allelic conditions and patients may have the possibility of an increased risk for the associated *SUFU* cancer phenotypes. In summary, genetic evidence was scored for 1 point and experimental evidence was scored for 5 points (6 points total) for *SUFU*-Ciliopathy, autosomal-recessive (MONDO:0005308). This gene-disease relationship is therefore classified as “Limited”. The underlying molecular mechanism is likely loss-of-function, leading to disrupted SHH-GLI3 signaling through the primary cilium. The genetic evidence is based on two probands from a single publication; therefore, this gene disease relationship has not been replicated over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date 03/22/2023 (SOP Version 9).

Inheritance Pattern: AD

Disease ID:MONDO:0007959

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0958189

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0007959

Submitter: ClinGen

There is abundant published evidence associating the SUFU gene with medulloblastoma since the gene-disease relationship was first proposed by Taylor et al. (2002). Multiple case level studies have been performed with medulloblastoma patients that have variants in the SUFU gene. PTCH1 and PTCH2 are also related to dominantly inherited NBCCS and medulloblastoma. The effect of medulloblastoma-derived mutant of SUFU on Hedgehog signaling activity had been shown in cell assays. Multiple SUFU deficient mouse models have been established to show consistent phenotypes with medulloblastoma patients. Sufu+/- mice develop a Gorlin-like skin phenotype. Patients with SUFU mutations can exhibit medulloblastoma and features of Gorlin syndrome. In conjunction with p53 loss, Sufu+/- mice developed tumors including medulloblastoma and rhabdomyosarcoma. All of these types of evidence are consistent with a definitive relationship between the SUFU gene and medulloblastoma.

Inheritance Pattern: AD

Disease ID:MONDO:0007959

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0033309

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0033309

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0033309

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0000665

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0009764

Submitter: Franklin by Genoox

15 individuals from six families with a clinical diagnosis of COMA underwent exome sequancing which revealed heterozygous variants of SUFU gene.