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. 2022 Aug;43(8):1097-1113.
doi: 10.1002/humu.24302. Epub 2021 Dec 2.

Recommendations by the ClinGen Rett/Angelman-like expert panel for gene-specific variant interpretation methods

Dianalee McKnight  1 , Lora Bean  2 , Izabela Karbassi  3 , Katelynn Beattie  4 , Thierry Bienvenu  5 , Hope Bonin  6 , Ping Fang  7 , John Chrisodoulou  8   9 , Michael Friez  10 , Maria Helgeson  1 , Rahul Krishnaraj  9   11 , Linyan Meng  7 , Lindsey Mighion  4 , Jeffrey Neul  12 , Alan Percy  13 , Simon Ramsden  6 , Huda Zoghbi  7 , Soma Das  14
Affiliations

Recommendations by the ClinGen Rett/Angelman-like expert panel for gene-specific variant interpretation methods

Dianalee McKnight et al. Hum Mutat. 2022 Aug.

Abstract

The genes MECP2, CDKL5, FOXG1, UBE3A, SLC9A6, and TCF4 present unique challenges for current ACMG/AMP variant interpretation guidelines. To address those challenges, the Rett and Angelman-like Disorders Variant Curation Expert Panel (Rett/AS VCEP) drafted gene-specific modifications. A pilot study was conducted to test the clarity and accuracy of using the customized variant interpretation criteria. Multiple curators obtained the same interpretation for 78 out of the 87 variants (~90%), indicating appropriate usage of the modified guidelines the majority of times by all the curators. The classification of 13 variants changed using these criteria specifications compared to when the variants were originally curated and as present in ClinVar. Many of these changes were due to internal data shared from laboratory members however some changes were because of changes in strength of criteria. There were no two-step classification changes and only 1 clinically relevant change (Likely pathogenic to VUS). The Rett/AS VCEP hopes that these gene-specific variant curation rules and the assertions provided help clinicians, clinical laboratories, and others interpret variants in these genes but also other fully penetrant, early-onset genes associated with rare disorders.

Keywords: Angelman syndrome; Christianson syndrome; Pitt-Hopkins syndrome; Rett syndrome; guidelines; variant interpretation.

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Conflict of interest statement

Conflict of Interests:

DM, LB, IK, KB, TB, PF, JC, MF, MH, LM, LM, SR, and SD are employees of fee-for-service diagnostic laboratories. AP is a consultant for Anavex Pharmaceuticals and Acadia Pharmaceuticals. LM holds a U.S. Patent 9,617,539, “Modulation of UBE3A-ATS expression”.

Figures

Figure 1:
Figure 1:
Diagrammatic representation of PVS1 cutoffs for each gene. Cutoffs for nonsense and frameshift variants are indicated in red. In-frame exons for each gene are indicated in blue with the respective PVS1 strengths indicated for deletion/skipping of these exons also in blue. PVS1 strengths for variants affecting the initiation codon are indicated in green. MECP2: NM_004992.3 / ENST00000303391.10; UBE3A: NM_130838.4 / ENST00000438097.6; CDKL5: NM_003159.2 / ENST00000379996.7 (top), NM_001323289.2 / ENST00000623535.1 (bottom); FOXG1: NM_005249.4 / ENST00000313071.6; SLC9A6: NM_006359.2 / ENST00000370698.7; TCF4: NM_001083962.1 / ENST00000354452.7
See this image and copyright information in PMC

References

    1. Abou Tayoun AN, Pesaran T, DiStefano MT, Oza A, Rehm HL, Biesecker LG, … ClinGen Sequence Variant Interpretation Working Group (ClinGen SVI). (2018). Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. Human Mutation, 39(11), 1517–1524. - PMC - PubMed
    1. Adkins NL, & Georgel PT (2011). MeCP2: structure and function. Biochemistry and Cell Biology = Biochimie et Biologie Cellulaire, 89(1), 1–11. - PubMed
    1. Amiel J, Rio M, de Pontual L, Redon R, Malan V, Boddaert N, … Colleaux L (2007). Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction. American Journal of Human Genetics, 80(5), 988–993. - PMC - PubMed
    1. Ariani F, Hayek G, Rondinella D, Artuso R, Mencarelli MA, Spanhol-Rosseto A, … Renieri A (2008). FOXG1 is responsible for the congenital variant of Rett syndrome. American Journal of Human Genetics, 83(1), 89–93. - PMC - PubMed
    1. Bienvenu T, Carrié A, de Roux N, Vinet MC, Jonveaux P, Couvert P, … Chelly J (2000). MECP2 mutations account for most cases of typical forms of Rett syndrome. Human Molecular Genetics, 9(9), 1377–1384. - PubMed

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