Heterozygous truncating variants in SUFU cause congenital ocular motor apraxia

Simone Schröder,Janine Altmüller,Saskia Biskup,Ingrid Bader,Steffi Dreha-Kulaczewski,Andrea Bevot,Johannes A Mayr,Saskia B Wortmann,Sarah Wente-Schulz,Georg Christoph Korenke ,Martin Preisel,Eugen Boltshauser,Raimund Kottke,Heidi Hahn,Yun Li,Sandra P Toelle,Gökhan Yiğit ,Bernd Wollnik,Anja Uhmann,Knut Brockmann

doi:10.1038/s41436-020-00979-w

Abstract

PurposeThis study aimed to delineate the genetic basis of congenital ocular motor apraxia (COMA) in patients not otherwise classifiable. MethodsWe 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. ResultsIn 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. ConclusionTaken together, our data imply that the clinical phenotype associated with heterozygous truncating germline variants in SUFU is a forme fruste of Joubert syndrome.

Highlights

The term congenital ocular motor apraxia (COMA), introduced by Cogan in 1952, designates the inability to initiate saccades, i.e., the eye movements performing rapid gaze shift
Taken together, our data imply that the clinical phenotype associated with heterozygous truncating germline variants in Suppressor of Fused (SUFU) is a forme fruste of Joubert syndrome
In a previous study aimed at a nosological delineation of COMA, we investigated a cohort of 21 patients diagnosed as having COMA.[12]

Summary

Introduction

The term congenital ocular motor apraxia (COMA), introduced by Cogan in 1952, designates the inability to initiate saccades, i.e., the eye movements performing rapid gaze shift. In his original report, Cogan described four children with a distinct disturbance of voluntary horizontal gaze characterized by the “inability to turn the eyes voluntarily in a direction for which there is full involuntary...control” accompanied by compensatory, jerky head movements.[1] COMA usually affects horizontal, but rarely vertical saccades. No gene associated with isolated COMA (OMIM 257550) has been identified yet

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