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Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe Mendelian disease gene.
Hum Mol Genet. 2015 May 01; 24(9):2594-603.HM

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.Trp1088Leufs*16) 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.

Authors+Show Affiliations

Medical Genetics Center, Cairo 11566, Egypt, Children's Hospital, Ain Shams University, Cairo 11566, Egypt.Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA.Institute of Human Genetics, University Hospital of Cologne, 50931 Cologne, Germany.Institute of Human Genetics, University Hospital of Cologne, 50931 Cologne, Germany.Medical Genetics Center, Cairo 11566, Egypt, Children's Hospital, Ain Shams University, Cairo 11566, Egypt.Cologne Center for Genomics (CCG) and Centre for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.Cologne Center for Genomics (CCG) and Centre for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany.Institute of Human Genetics, University Hospital of Cologne, 50931 Cologne, Germany.Institute of Human Genetics, University Hospital of Cologne, 50931 Cologne, Germany.Institute of Human Genetics, University Hospital of Cologne, 50931 Cologne, Germany, Cologne Center for Genomics (CCG) and Centre for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.Cologne Center for Genomics (CCG) and Centre for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.Cologne Center for Genomics (CCG) and Centre for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.Department of Radiology, University of Cologne, 50937 Cologne, Germany.Laboratory of Computational Chemistry and Drug Design, Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, 518000 Shenzhen, P. R. China.Laboratory of Computational Chemistry and Drug Design, Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, 518000 Shenzhen, P. R. China, College of Chemistry, Peking University, 100871 Beijing, P. R. China.Department of Clinical Genetics, National Research Centre, Cairo 11566, Egypt.Department of Clinical Genetics, National Research Centre, Cairo 11566, Egypt.Laboratory of Neurogenetics, Howard Hughes Medical Institute, Department of Neurosciences, University of California, La Jolla, San Diego, CA 92093, USA.Department of Paediatric Neurology, University Children's Hospital of Zurich, 8032 Zurich, Switzerland and.Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA.Institute of Human Genetics, University Hospital of Cologne, 50931 Cologne, Germany, Center for Human Genetics, Bioscientia, 55218 Ingelheim, Germany hanno.bolz@uk-koeln.de.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25616960

Citation

Elsayed, Solaf M., et al. "Non-manifesting AHI1 Truncations Indicate Localized Loss-of-function Tolerance in a Severe Mendelian Disease Gene." Human Molecular Genetics, vol. 24, no. 9, 2015, pp. 2594-603.
Elsayed SM, Phillips JB, Heller R, et al. Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe Mendelian disease gene. Hum Mol Genet. 2015;24(9):2594-603.
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., ... Bolz, H. J. (2015). Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe Mendelian disease gene. Human Molecular Genetics, 24(9), 2594-603. https://doi.org/10.1093/hmg/ddv022
Elsayed SM, et al. Non-manifesting AHI1 Truncations Indicate Localized Loss-of-function Tolerance in a Severe Mendelian Disease Gene. Hum Mol Genet. 2015 May 1;24(9):2594-603. PubMed PMID: 25616960.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe Mendelian disease gene. AU - Elsayed,Solaf M, AU - Phillips,Jennifer B, AU - Heller,Raoul, AU - Thoenes,Michaela, AU - Elsobky,Ezzat, AU - Nürnberg,Gudrun, AU - Nürnberg,Peter, AU - Seland,Saskia, AU - Ebermann,Inga, AU - Altmüller,Janine, AU - Thiele,Holger, AU - Toliat,Mohammad, AU - Körber,Friederike, AU - Hu,Xue-Jia, AU - Wu,Yun-Dong, AU - Zaki,Maha S, AU - Abdel-Salam,Ghada, AU - Gleeson,Joseph, AU - Boltshauser,Eugen, AU - Westerfield,Monte, AU - Bolz,Hanno J, Y1 - 2015/01/23/ PY - 2014/10/16/received PY - 2015/01/21/accepted PY - 2015/1/25/entrez PY - 2015/1/27/pubmed PY - 2015/12/23/medline SP - 2594 EP - 603 JF - Human molecular genetics JO - Hum. Mol. Genet. VL - 24 IS - 9 N2 - 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.Trp1088Leufs*16) 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. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/25616960/Non_manifesting_AHI1_truncations_indicate_localized_loss_of_function_tolerance_in_a_severe_Mendelian_disease_gene_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddv022 DB - PRIME DP - Unbound Medicine ER -