Submission Details

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).