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., Wu, Y.D., Zaki, M.S., Abdel-Salam, G., Gleeson, J., Boltshauser, E., Westerfield, M., Bolz, H.J.
Human molecular genetics   24(9): 2594-603 (Journal)
Registered Authors
Phillips, Jennifer, Westerfield, Monte
MeSH Terms
  • Abnormalities, Multiple/diagnosis
  • Abnormalities, Multiple/genetics
  • Adaptor Proteins, Signal Transducing/chemistry
  • Adaptor Proteins, Signal Transducing/genetics*
  • Adaptor Proteins, Signal Transducing/metabolism*
  • Animals
  • Brain/pathology
  • Cerebellum/abnormalities
  • Chromosome Mapping
  • Consanguinity
  • DNA Mutational Analysis
  • Disease Models, Animal
  • Evolution, Molecular
  • Exome
  • Eye Abnormalities/diagnosis
  • Eye Abnormalities/genetics
  • Female
  • Gene Order
  • Genes, Recessive
  • Genetic Association Studies*
  • Genetic Loci
  • Heterozygote
  • High-Throughput Nucleotide Sequencing
  • Homozygote
  • Humans
  • Kidney Diseases, Cystic/diagnosis
  • Kidney Diseases, Cystic/genetics
  • Magnetic Resonance Imaging
  • Male
  • Models, Molecular
  • Mutation*
  • Pedigree
  • Protein Conformation
  • Retina/abnormalities
  • Zebrafish/genetics
25616960 Full text @ Hum. Mol. Genet.
Determination of variant pathogenicity represents a major challenge in the era of high-throughput sequencing. Erroneous categorization may result if variants affect genes which 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.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes