Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling

Eur J Hum Genet. 2018 Feb;26(2):197-209. doi: 10.1038/s41431-017-0019-9.

Reza Asadollahi ¹, Justin E Strauss ², Martin Zenker ³, Oliver Beuing ⁴, Simon Edvardson ⁵, Orly Elpeleg ⁶, Tim M Strom ⁷, Pascal Joset ¹, Dunja Niedrist ¹, Christine Otte ¹, Beatrice Oneda ¹, Paranchai Boonsawat ¹, Silvia Azzarello-Burri ¹, Deborah Bartholdi ¹, Michael Papik ¹, Markus Zweier ¹, Cordula Haas ⁸, Arif B Ekici ⁹, Alessandra Baumer ¹, Eugen Boltshauser ¹⁰, Katharina Steindl ¹, Michael Nothnagel ¹¹, Albert Schinzel ¹, Esther T Stoeckli ² ¹², Anita Rauch ¹³ ¹⁴ ¹⁵

Affiliations

1 Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
2 Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
3 Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
4 Institute of Neuroradiology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
5 Pediatric Neurology Unit, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel.
6 Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
7 Institute of Human Genetics, Technische Universität München, Munich, Germany.
8 Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland.
9 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
10 Department of Pediatric Neurology, University Children's Hospital, Zurich, Switzerland.
11 Cologne Center for Genomics, Department of Statistical Genetics and Bioinformatics, University of Cologne, Cologne, Germany.
12 Neuroscience Center Zurich, University of Zurich, Zurich, Switzerland.
13 Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland. anita.rauch@medgen.uzh.ch.
14 Neuroscience Center Zurich, University of Zurich, Zurich, Switzerland. anita.rauch@medgen.uzh.ch.
15 Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland. anita.rauch@medgen.uzh.ch.

PMID: 29321670 DOI: 10.1038/s41431-017-0019-9

Abstract

Acrocallosal syndrome (ACLS) is an autosomal recessive neurodevelopmental disorder caused by KIF7 defects and belongs to the heterogeneous group of ciliopathies related to Joubert syndrome (JBTS). While ACLS is characterized by macrocephaly, prominent forehead, depressed nasal bridge, and hypertelorism, facial dysmorphism has not been emphasized in JBTS cohorts with molecular diagnosis. To evaluate the specificity and etiology of ACLS craniofacial features, we performed whole exome or targeted Sanger Sequencing in patients with the aforementioned overlapping craniofacial appearance but variable additional ciliopathy features followed by functional studies. We found (likely) pathogenic variants of KIF7 in 5 out of 9 families, including the original ACLS patients, and delineated 1000 to 4000-year-old Swiss founder alleles. Three of the remaining families had (likely) pathogenic variants in the JBTS gene C5orf42, and one patient had a novel de novo frameshift variant in SHH known to cause autosomal dominant holoprosencephaly. In accordance with the patients' craniofacial anomalies, we showed facial midline widening after silencing of C5orf42 in chicken embryos. We further supported the link between KIF7, SHH, and C5orf42 by demonstrating abnormal primary cilia and diminished response to a SHH agonist in fibroblasts of C5orf42-mutated patients, as well as axonal pathfinding errors in C5orf42-silenced chicken embryos similar to those observed after perturbation of Shh signaling. Our findings, therefore, suggest that beside the neurodevelopmental features, macrocephaly and facial widening are likely more general signs of disturbed SHH signaling. Nevertheless, long-term follow-up revealed that C5orf42-mutated patients showed catch-up development and fainting of facial features contrary to KIF7-mutated patients.

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