Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comment
. 2022 Aug 4;185(16):2850-2852.
doi: 10.1016/j.cell.2022.07.005.

The gene dose makes the disease

Corrine Smolen  1 , Santhosh Girirajan  2
Affiliations
Comment

The gene dose makes the disease

Corrine Smolen et al. Cell. .

Abstract

A long-standing challenge in genomics has been to identify causal genes within rare copy-number variant regions that are intolerant to altered dosage. In this issue, Collins et al. perform a meta-analysis of almost a million individuals to identify dosage-sensitive segments and genes conferring risk for a range of disease phenotypes.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Figures

Figure 1.
Figure 1.. Mechanisms of pathogenicity of disease for dosage-sensitive genes within CNVs.
(A) Phenotypes observed in both deletions and duplications can be caused by a single gene, such as RAI1 in Smith-Magenis and Potocki-Lupski syndromes. (B) Multiple dosage-sensitive genes within a CNV region can also individually contribute to distinct phenotypes, as in Williams-Bueren syndrome. Individual genes could be either bidirectionally sensitive or uniquely haploinsufficient (gene B) or triplosensitive (gene A). (C) Phenotypes in CNV disorders can also result from interactions of multiple dosage-sensitive genes, as reported in model systems for 16p11.2 deletion. (D) Interactions of one or more dosage-sensitive genes with modifier variants in the genetic background, including both rare and common variants, can also modulate CNV phenotypes. (E) The expression of dosage-sensitive genes can be affected by parental imprinting, as in Prader-Willi and Angelman syndromes, where the parent of origin of the CNV allele affects the manifested phenotypes.
See this image and copyright information in PMC

Comment on

  • A cross-disorder dosage sensitivity map of the human genome.
    Collins RL, Glessner JT, Porcu E, Lepamets M, Brandon R, Lauricella C, Han L, Morley T, Niestroj LM, Ulirsch J, Everett S, Howrigan DP, Boone PM, Fu J, Karczewski KJ, Kellaris G, Lowther C, Lucente D, Mohajeri K, Nõukas M, Nuttle X, Samocha KE, Trinh M, Ullah F, Võsa U; Epi25 Consortium; Estonian Biobank Research Team; Hurles ME, Aradhya S, Davis EE, Finucane H, Gusella JF, Janze A, Katsanis N, Matyakhina L, Neale BM, Sanders D, Warren S, Hodge JC, Lal D, Ruderfer DM, Meck J, Mägi R, Esko T, Reymond A, Kutalik Z, Hakonarson H, Sunyaev S, Brand H, Talkowski ME. Collins RL, et al. Cell. 2022 Aug 4;185(16):3041-3055.e25. doi: 10.1016/j.cell.2022.06.036. Epub 2022 Aug 1. Cell. 2022. PMID: 35917817 Free PMC article.

References

    1. Albers CA, Paul DS, Schulze H, Freson K, Stephens JC, Smethurst PA, Jolley JD, Cvejic A, Kostadima M, Bertone P, Breuning MH, Debili N, Deloukas P, Favier R, Fiedler J, Hobbs CM, Huang N, Hurles ME, Kiddle G, … Ghevaert C (2012). Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nature Genetics, 44(4), 435–439, S1-2. 10.1038/ng.1083 - DOI - PMC - PubMed
    1. Coe BP, Stessman HAF, Sulovari A, Geisheker MR, Bakken TE, Lake AM, Dougherty JD, Lein ES, Hormozdiari F, Bernier RA, & Eichler EE (2019). Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity. Nature Genetics, 51(1), 106–116. 10.1038/s41588-018-0288-4 - DOI - PMC - PubMed
    1. Collins RL, Glessner JT, Porcu E, Lepamets M, Brandon R, Lauricalla C, Han L, Morley T, Niestroj L-M, Ulirsch J, Everett S, Howrigan DP, Boone PM, Fu J, Karczewski KJ, Kellaris G, Lowther C, Lucente D, Mohajeri K, … Talkowski ME (2022). A cross-disorder dosage sensitivity map of the human genome. Cell. - PMC - PubMed
    1. Iyer J, & Girirajan S (2015). Gene discovery and functional assessment of rare copy-number variants in neurodevelopmental disorders. Briefings in Functional Genomics, 14(5), 315–328. 10.1093/bfgp/elv018 - DOI - PubMed
    1. Iyer J, Singh MD, Jensen M, Patel P, Pizzo L, Huber E, Koerselman H, Weiner AT, Lepanto P, Vadodaria K, Kubina A, Wang Q, Talbert A, Yennawar S, Badano J, Manak JR, Rolls MM, Krishnan A, & Girirajan S (2018). Pervasive genetic interactions modulate neurodevelopmental defects of the autism-associated 16p11.2 deletion in Drosophila melanogaster. Nature Communications, 9(1), 2548. 10.1038/s41467-018-04882-6 - DOI - PMC - PubMed

Publication types

LinkOut - more resources