Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains PMID: 28628100

GLP-1 and Obesity Research

2026-08-18

Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains

Nat Neurosci. 2017 Aug;20(8):1043-1051. doi: 10.1038/nn.4589.

Madeleine R Geisheker ¹ , Gabriel Heymann ² ³ , Tianyun Wang ⁴ , Bradley P Coe ¹ , Tychele N Turner ¹ , Holly A F Stessman ¹ , Kendra Hoekzema ¹ , Malin Kvarnung ⁵ ⁶ , Marie Shaw ⁷ , Kathryn Friend ⁷ ⁸ , Jan Liebelt ⁹ , Christopher Barnett ⁹ ¹⁰ , Elizabeth M Thompson ⁹ ¹¹ , Eric Haan ⁹ ¹¹ , Hui Guo ⁴ , Britt-Marie Anderlid ⁵ ⁶ , Ann Nordgren ⁵ ⁶ , Anna Lindstrand ⁵ ⁶ , Geert Vandeweyer ¹² , Antonino Alberti ¹³ , Emanuela Avola ¹³ , Mirella Vinci ¹⁴ , Stefania Giusto ¹⁵ , Tiziano Pramparo ¹⁶ , Karen Pierce ¹⁶ , Srinivasa Nalabolu ¹⁶ , Jacob J Michaelson ¹⁷ , Zdenek Sedlacek ¹⁸ , Gijs W E Santen ¹⁹ , Hilde Peeters ²⁰ , Hakon Hakonarson ²¹ ²² ²³ , Eric Courchesne ¹⁶ , Corrado Romano ¹³ , R Frank Kooy ¹² , Raphael A Bernier ³ , Magnus Nordenskjöld ⁵ ⁶ , Jozef Gecz ⁷ ²⁴ , Kun Xia ⁴ , Larry S Zweifel ² ³ , Evan E Eichler ¹ ²⁵

Affiliations

1. Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
2. Department of Pharmacology, University of Washington, Seattle, Washington, USA.
3. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.
4. The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
5. Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
6. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
7. Robinson Research Institute and the University of Adelaide at the Women's and Children's Hospital, North Adelaide, South Australia, Australia.
8. SA Pathology, Adelaide, South Australia, Australia.
9. South Australian Clinical Genetics Service, SA Pathology (at Women's and Children's Hospital), Adelaide, South Australia, Australia.
10. School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.
11. School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
12. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
13. Unit of Pediatrics &Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
14. Laboratory of Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
15. Unit of Neurology, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
16. University of California, San Diego, Autism Center of Excellence, La Jolla, California, USA.
17. Department of Psychiatry, The University of Iowa, Iowa City, Iowa, USA.
18. Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
19. Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
20. Centre for Human Genetics, KU Leuven and Leuven Autism Research, Leuven, Belgium.
21. Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
22. Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
23. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
24. South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
25. Howard Hughes Medical Institute, Seattle, Washington, USA.

Abstract

Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted Sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.