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

Abstract

Background: Joubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%-75%.In 2018, we reported homozygous hypomorphic missense variants of the SUFU gene in two families with mild JS. Recently, heterozygous truncating SUFU variants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies.

Methods: We reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes.

Results: Heterozygous truncating and splice-site SUFU variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents.

Conclusion: Heterozygous truncating or splice-site SUFU variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk.

Keywords: and neonatal diseases and abnormalities; central nervous system diseases; cerebellar diseases; congenital; early diagnosis; genetic variation; hereditary.

Figure 1

Schematic of the SUFU gene (NM_001178133.1) and variants reported so far in patients with mild JS, COMA, Gorlin syndrome or cancer. SUFU gene structure and location of reported variants. Upper panel shows heterozygous truncating and canonical splice site variants identified in the present study, as well as heterozygous LOF variants identified in patients with COMA (boxed), and homozygous missense variants identified in patients with JS (underlined). Lower panel shows heterozygous truncating and canonical splice site variants identified in patients with Gorlin syndrome or cancer. Note that three variants recurred in patients with neurodevelopmental phenotypes and in patients with cancer. COMA, congenital ocular motor apraxia; JS, Joubert syndrome.

Figure 2

Representative MRIs of cerebellar vermis and SCPs in healthy control, SUFU heterozygous carriers and JS with ‘mild’ and ‘typical’ MTS. Four representative T1-weighted MRIs (arranged in horizontal rows) are shown from one asymptomatic control (10–15 years old, A–D), two individuals (0–5 years old) with SUFU LOF heterozygous variants (families COR280 and COR552) (E–H), and (I–L), one individual with JS associated due to homozygous NPHP1 deletion (15–20 years old, (M–P)), and one individual with JS associated with biallelic pathogenic AHI1 variants (0–5 years old, (Q–T)) (all unpublished). The first column (A, E, I, M, Q) shows axial views at the level of the upper cerebellum, demonstrating folial dysplasia (arrow) in all individuals except the control. The second column (B, F, J, N, R) illustrates axial views at the level of the SCPs (arrows), which are more prominent (longer, thicker)) illustrates axial views at the level of the SCPs (arrows), which are more prominent (longer, thicker) compared with normal (mild MTS in row 2–4, typical MTS in row 5). The third column (C, G, K, O, S) shows parasagittal sections demonstrating thick and horizontal SCPs in all individuals shown except the healthy control (arrow). The fourth column (D, H, L, P, T)illustrates coronal images revealing variable irregular folia and vermis splitting (arrows) in all individuals shown except the control. JB, Joubert syndrome; MTS, molar tooth sign; SCP, superior cerebellar peduncle.