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Matias Wagner1,2,3, Dominik S Westphal1,2, Iris Hannibal4, Johannes A. Mayr5, Tim M. Strom1,2, Thomas Meitinger1,2, Holger Prokisch1,2, Saskia B. Wortmann1,2,5
1. Institute of Human Genetics, Technical University Munich, Munich, Germany;
2. Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany;
3. Institute of Neurogenomics, Helmholtz Zentrum Munich, Neuherberg, Germany
4. Dr. von Hauner Children’s Hospital, Ludwig-Maximilians University, Munich, Germany
5. Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria
Biallelic mutations in KIAA0586 have been related to Joubert syndrome (JBTS) 23 and as the most frequent disease causing variant c.428del (p.Arg143Lysfs*4) was identified.1 However, the allele frequency of 0.003117 and two homozygotes in the gnomAD dataset as well as additional reports of healthy carriers have questioned the variant’s pathogenicity.2, 3 Pauli et al. have recently hypothesized that c.428del is a hypomorphic allele which is only causing JBTS in compound heterozygosity with other mutations.
In 15,000 in-house exome data sets, we have identified three individuals harboring c.428del in a homozygous state. In two, we identified other variants sufficiently explaining the phenotype: In a 6 year old girl with global developmental delay and progressive myoclonic astatic epilepsy, we identified a de novo variant c.2683del, p.Ser895Le...
In 15,000 in-house exome data sets, we have identified three individuals harboring c.428del in a homozygous state. In two, we identified other variants sufficiently explaining the phenotype: In a 6 year old girl with global developmental delay and progressive myoclonic astatic epilepsy, we identified a de novo variant c.2683del, p.Ser895Leufs*14 in KIAA2022 (NM_001008537.2, MIM#300912: mental retardation 98). In a 56 year old male patient from a large family with X-linked mental retardation, a hemizygous missense variant in FRMPD4 (NM_014728.3): c.41861G>T, p.Asp621Tyr was identified. In the third case, a 5 year old boy with medically unexplained isolated fatigue we did not identify other variants than c.428del in KIAA0586.
However, in a 3 year old male with global delays, truncal hypotonia, ataxia and eye movement disorders we identified the variant c.428del in compound heterozygosity with c.863_864del, p.Gln288Argfs*7 (NM_014749.3). As the clinical findings resemble the core phenotype of JBTS23, we consider the combination of these variants causal for the patient’s condition.4
Analysis of RNA sequencing data from two heterozygous carriers indicates that mutant transcripts escape nonsense mediated decay. Residual function of the c.428del KIAA0586 allele most likely originates from the use of an alternative start codon (Supplementary figure).
These findings further strengthen the hypothesis of Pauli et al. that c.428del is indeed a hypomorphic allele which is only disease causing in trans with a loss of function mutation.
1. Bachmann-Gagescu R, et al. KIAA0586 is Mutated in Joubert Syndrome. Human mutation 36, 831-835 (2015).
2. Pauli S, et al. Homozygosity for the c.428delG variant in KIAA0586 in a healthy individual: implications for molecular testing in patients with Joubert syndrome. Journal of medical genetics, (2018).
3. Sulem P, et al. Identification of a large set of rare complete human knockouts. Nature genetics 47, 448-452 (2015).
4. Bachmann-Gagescu R, et al. Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity. Journal of medical genetics 52, 514-522 (2015).