Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe Mendelian disease gene

Elsayed, S.M.; Phillips, J.B.; Heller, R.; Thoenes, M.; Elsobky, E.; Nürnberg, G.; Nürnberg, P.; Seland, S.; Ebermann, I.; Altmüller, J.; Thiele, H.; Toliat, M.; Körber, F.; Hu, X.J.; Wu, Y.D.; Zaki, M.S.; Abdel-Salam, G.; Gleeson, J.; Boltshauser, E.; Westerfield, M.; Bolz, H.J.

Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe Mendelian disease gene

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Item Type:	Article
Title:	Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe Mendelian disease gene
Creators Name:	Elsayed, S.M., Phillips, J.B., Heller, R., Thoenes, M., Elsobky, E., Nürnberg, G., Nürnberg, P., Seland, S., Ebermann, I., Altmüller, J., Thiele, H., Toliat, M., Körber, F., Hu, X.J., Wu, Y.D., Zaki, M.S., Abdel-Salam, G., Gleeson, J., Boltshauser, E., Westerfield, M. and Bolz, H.J.
Abstract:	Determination of variant pathogenicity represents a major challenge in the era of high-throughput sequencing. Erroneous categorization may result if variants affect genes that are in fact dispensable. We demonstrate that this also applies to rare, apparently unambiguous truncating mutations of an established disease gene. By whole-exome sequencing (WES) in a consanguineous family with congenital non-syndromic deafness, we unexpectedly identified a homozygous nonsense variant, p.Arg1066, in AHI1, a gene associated with Joubert syndrome (JBTS), a severe recessive ciliopathy. None of four homozygotes expressed any signs of JBTS, and one of them had normal hearing, which also ruled out p.Arg1066 as the cause of deafness. Homozygosity mapping and WES in the only other reported JBTS family with a homozygous C-terminal truncation (p.Trp1088Leufs16) confirmed AHI1 as disease gene, but based on a more N-terminal missense mutation impairing WD40-repeat formation. Morpholinos against N-terminal zebrafish Ahi1, orthologous to where human mutations cluster, produced a ciliopathy, but targeting near human p.Arg1066 and p.Trp1088 did not. Most AHI1 mutations in JBTS patients result in truncated protein lacking WD40-repeats and the SH3 domain; disease was hitherto attributed to loss of these protein interaction modules. Our findings indicate that normal development does not require the C-terminal SH3 domain. This has far-reaching implications, considering that variants like p.Glu984 identified by preconception screening (‘Kingsmore panel’) do not necessarily indicate JBTS carriership. Genomes of individuals with consanguineous background are enriched for homozygous variants that may unmask dispensable regions of disease genes and unrecognized false positives in diagnostic large-scale sequencing and preconception carrier screening.
Keywords:	Animal Disease Models, Brain, Cerebellum, Chromosome Mapping, Consanguinity, Cystic Kidney Diseases, DNA Mutational Analysis, Exome, Eye Abnormalities, Gene Order, Genetic Association Studies, Genetic Loci, Heterozygote, High-Throughput Nucleotide Sequencing, Homozygote, Magnetic Resonance Imaging, Molecular Evolution, Molecular Models, Multiple Abnormalities, Mutation, Pedigree, Protein Conformation, Recessive Genes, Retina, Signal Transducing Adaptor Proteins, Vesicular Transport Adaptor Proteins, Animals, Zebrafish
Source:	Human Molecular Genetics
ISSN:	0964-6906
Publisher:	Oxford University Press
Volume:	24
Number:	9
Page Range:	2594-2603
Date:	1 May 2015
Official Publication:	https://doi.org/10.1093/hmg/ddv022
PubMed:	View item in PubMed

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