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

Joubert syndrome (JS) is a recessively inherited ciliopathy characterized by congenital ocular motor apraxia (COMA), developmental delay, intellectual disability, ataxia, multiorgan involvement and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known, with 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.

We reanalyzed NGS data in two cohorts comprising 1097 probands referred for genetic testing of JS genes. Heterozygous truncating and splice-site SUFU variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in eight asymptomatic parents. The majority of affected children presented with the same constellation of neurological features seen at the mildest end of the JS spectrum, characterized by early onset hypotonia persisting in infancy, COMA, mild motor and speech delay and mild truncal and limb ataxia.

Ataxia occurred in over 60% of the patients, while only about one third eventually manifested intellectual disability. Abnormal neonatal breathing was reported only in a minority of patients. Of note, macrocephaly was present in 19 out of 22 children, while extra-neurological involvement was extremely rare. Attention-Deficit/Hyperactivity Disorder, autism traits, obsessive-compulsive disrdr and other behavioral defects were reported in a minority of patient.