AUTHOR=Luo Minna , He Ruida , Lin Zaisheng , Shen Yue , Zhang Guangyu , Cao Zongfu , Lu Chao , Meng Dan , Zhang Jing , Ma Xu , Cao Muqing 

TITLE=Novel Compound Heterozygous Variants in MKS1 Leading to Joubert Syndrome

JOURNAL=Frontiers in Genetics

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.576235

DOI=10.3389/fgene.2020.576235

ISSN=1664-8021

ABSTRACT=<p>Joubert syndrome (JBTS) and Meckel–Gruber syndrome (MKS) are rare recessive disorders caused by defects of cilia, and they share overlapping clinical features and allelic loci. Mutations of <italic>MKS1</italic> contribute approximately 7% to all MKS cases and are found in some JBTS patients. Here, we describe a JBTS patient with two novel mutations of <italic>MKS1</italic>. Whole exome sequencing (WES) revealed c.191-1G &gt; A and c.1058delG compound heterozygous variants. The patient presented with typical cerebellar vermis hypoplasia, hypotonia, and developmental delay, but without other renal/hepatic involvement or polydactyly. Functional studies showed that the c.1058delG mutation disrupts the B9 domain of MKS1, attenuates the interactions with B9D2, and impairs its ciliary localization at the transition zone (TZ), indicating that the B9 domain of MKS1 is essential for the integrity of the B9 protein complex and localization of MKS1 at the TZ. This work expands the mutation spectrum of <italic>MKS1</italic> and elucidates the clinical heterogeneity of <italic>MKS1</italic>-related ciliopathies.</p>