Heterozygous truncating variants in SUFU cause congenital ocular motor apraxia

Abstract

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.

SUFU haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum

“…By including the two additional potential carriers, who are both female (the sister of UW423-1 and UW427-1 reported with COMA, and the mother of UW435-3 reported with macrocephaly), the male proportion among carriers could even drop to 25%. In the study by Schröder et al , 10 out of 13 (77%) manifesting carriers were male, while the only two clinically unaffected carriers were both female, in line with our observation 11. Such preponderance of male sex in manifesting versus non-manifesting carriers is intriguing, suggesting that sex-related factors may affect the penetrance of SUFU variants.…”

“…14 Interestingly, of the formerly reported 15 patients diagnosed with COMA and carrying heterozygous truncating SUFU variants, nearly all presented overlapping neurological features, including developmental and/or speech delay, early onset truncal and gait ataxia and, to a lesser extent, learning disability, indicating that these patients and the patients reported here are affected by the same neurodevelopmental condition related to SUFU haploinsufficiency. 11 Further supporting this observation, the imaging pattern is also highly consistent: indeed, all patients in this study as well as those reported by Schröder et al 11 showed a combination of vermis hypoplasia, superior cerebellar folial dysplasia and abnormalities of the SCPs, which variably appear long, thick and horizontal. This pattern often results in a 'mild MTS' appearance, similar to what has already been reported in patients with JS carrying pathogenic variants in other genes, including NPHP1, CPLANE1, CBY1 and FAM149B1 (figure 2M-P).…”

“…A possible clinical clue for SUFU -related conditions is represented by macrocephaly of variable degree; however, it must be noted that a large head circumference has been reported as a common finding in young children with JS, often resolving with age 14. Interestingly, of the formerly reported 15 patients diagnosed with COMA and carrying heterozygous truncating SUFU variants, nearly all presented overlapping neurological features, including developmental and/or speech delay, early onset truncal and gait ataxia and, to a lesser extent, learning disability, indicating that these patients and the patients reported here are affected by the same neurodevelopmental condition related to SUFU haploinsufficiency 11…”

“…Of note, several individuals also had developmental delay, mild learning disability, mild ataxia and abnormal vermis and SCPs on MRI reanalysis, questioning whether a subset of COMA is actually JS. 11 Here we report de novo or inherited heterozygous truncating or canonical splice site SUFU variants in 22 patients from 17 families, initially referred for genetic testing of JS-related genes due to suggestive clinical and/or neuroimaging features. As a result, we delineate a consistent neurodevelopmental syndrome encompassing the mild end of the JS spectrum, associated with presumed haploinsufficiency of the SUFU gene.…”

“…Recently, heterozygous truncating SUFU variants were identified in 15 individuals from six families presenting with COMA, a congenital developmental disturbance of voluntary gaze characterised by the inability to initiate saccades, mainly horizontal. Of note, several individuals also had developmental delay, mild learning disability, mild ataxia and abnormal vermis and SCPs on MRI reanalysis, questioning whether a subset of COMA is actually JS 11…”