RT Journal Article SR Electronic T1 Homozygosity for the c.428delG variant in KIAA0586 in a healthy individual: implications for molecular testing in patients with Joubert syndrome JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 261 OP 264 DO 10.1136/jmedgenet-2018-105470 VO 56 IS 4 A1 Silke Pauli A1 Janine Altmüller A1 Simone Schröder A1 Andreas Ohlenbusch A1 Steffi Dreha-Kulaczewski A1 Carsten Bergmann A1 Peter Nürnberg A1 Holger Thiele A1 Yun Li A1 Bernd Wollnik A1 Knut Brockmann YR 2019 UL http://jmg.bmj.com/content/56/4/261.abstract AB Background Joubert syndrome (JBTS) is a rare neurodevelopmental disorder with marked phenotypic variability and genetic heterogeneity. Homozygous or compound heterozygous mutations in the KIAA0586 gene on chromosome 14q23 are known to be associated with JBTS-23. The frameshift variant c.428delG is the most frequent KIAA0586 variant reported in JBTS-23; yet, homozygosity of this variant was observed in two patients with JBTS-23. However, homozygosity of the c.428delG variant was recently reported as well in one healthy individual.Objective To clarify whether the frameshift variant c.428delG in KIAA0586 is pathogenic in the homozygous state.Methods Whole-exome sequencing as well as RNA analysis were performed.Results We identified biallelic mutations, including the variant c.428delG and a splice site variant c.1413–1G>C, in KIAA0586 in two siblings with clinical and MRI features of JBTS. The c.1413–1G>C variant was inherited from the healthy father. The c.428delG variant was found in the healthy mother in a homozygous state in blood lymphocytes, hair root cells and buccal epithelial cells. RNA analysis revealed that the transcript harbouring the c.428delG variant was expressed in blood cells from the healthy mother, indicating that transcripts harbouring this variant elude the mechanism of nonsense-mediated mRNA decay.Conclusion Considering this and the high allele frequency of 0.003117 in the gnomAD database, we conclude that c.428delG represents a JBTS disease-causing variant only if present in compound heterozygous state with a more severe KIAA0586 variant, but not in a homozygous situation.