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

Abstract

BackgroundJoubert 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.MethodsWe reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes.ResultsHeterozygous 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.ConclusionHeterozygous 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.

Genotype–phenotype correlates in Joubert syndrome: A review

“…In a recent comprehensive review of 254 JS individuals with different eye phenotypes, OMA was the commonest ocularmotor abnormality in JS, associated with variants in most genes (Wang et al, 2018). Of note, patients with heterozygous SUFU variants may present with a spectrum of neurodevelopmental phenotypes encompassing congenital OMA and mild JS (Schröder et al, 2020;Serpieri et al, 2021).…”

“…JS is mainly inherited in an autosomal recessive fashion, with the exception of an X‐linked recessive form due to pathogenic variants in the OFD1 gene (Coene et al, 2009) and a recently reported autosomal dominant form due to truncating or splice‐site variants in the SUFU gene (Serpieri et al, 2021). Of note, almost all JS genes have also been implicated in other ciliopathies, such as Meckel syndrome (MKS), isolated nephronophthisis (NPHP), Leber congenital amaurosis (LCA), oral‐facial‐digital syndromes (OFDS), Bardet‐Biedl syndrome (BBS), and others.…”

Molecular Bases of Human Malformation Syndromes Involving the SHH Pathway: GLIA/R Balance and Cardinal Phenotypes

“…In mice, homozygous targeted disruption of Sufu led to embryonic lethality at mid gestation (~E9.5) with cephalic and neural tube defects [ 103 , 104 ]. Similarly, there have been no reports of complete functional loss of both alleles of SUFU in humans, and this genotype is expected to be embryonic lethal [ 105 , 106 ]. However, Mori et al reported that hypomorphic (partial loss of gene function) recessive variants in SUFU cause Joubert syndrome with cranio-facial and skeletal defects (JBTS32) in two families [ 105 ].…”

“…It was recently found that haploinsufficiency of SUFU (heterozygous LOF mutation) also presents with congenital ocular motor apraxia [ 109 ] and neurodevelopmental delay with the mild Joubert syndrome phenotype [ 106 ]. These phenotypes are a continuous spectrum and show incomplete penetrance in familial cases.…”

“…It is not clear what causes this discrepancy. Both syndromes are caused by LOF SUFU mutations, and some of these mutations occur both in patients with neurodevelopmental phenotypes and in patients with cancer [ 106 ], but these phenotypes do not overlap.…”