A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patient Ascertainment
2.2. Clinical Data Collection
2.3. Transcript
2.4. DNA Methylation
2.5. Analyses of Facial Features
2.5.1. Computer Vision Algorithms
2.5.2. Face2Gene
3. Results
3.1. DNA Methylation
3.2. Facial Analyses
3.2.1. Computer Vision Algorithms
3.2.2. Face2Gene
3.3. Variant Interpretation
3.3.1. Variants at the 5′ end of Exon 1 of ARID1B
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
Case 7
3.3.2. Splice Sites of in-Frame Exons or in-Frame Deletions in ARID1B
Case 8
Case 9
Case 10
3.3.3. Mosaicism in Parents
Case 11
Case 12
4. Discussion
4.1. Variable Expression
- Use caution interpreting LOF variants at the extreme 5′ and 3′ ends of a gene.
- If variants in related genes lead to the same signature, care must be taken to exclude the relevant variants in those genes.
4.2. Variant Location and the PVS1 Category
4.3. Transcript Choice
4.4. Incorporating New Developments into ACMG Guidelines for the Interpretation of Sequence Variants
4.4.1. Facial Analyses
4.4.2. DNA Methylation
4.4.3. Incorporating Suggested ACMG Updates
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Case | Exon | cDNA | Protein Change | Inheritance | Variant | GnomAD (1 May 2021) | DNA Methylation Pattern | Phenotype Suggestive for an ARID1B Related Disorder | Photograph Clusters with ARID1B Patients | CSS in Face2Gene (Rank/Similarity) | ACMG Criteria | Interpretation ACMG | Updated ACMG Criteria | Interpretation Updated ACMG | Expert Opinion |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 1 | c.3G > A | p.(Met1?) | Not maternal | Start codon | No | no BAFopathy | + | + | 2/0.32 | PVS1, PM2 | LP | PM2, PM7, PP4 | VUS | VUS |
2 | 1 | c.361C > T | p.(Gln121*) | Paternal | Nonsense | No | n.a. | +/− | n.a. | n.a. | PVS1, PM2 | LP | PM2, PM7 | VUS | VUS |
3 | 1 | c.363_364insG | p.(Gln122fs*110) | Unknown | Frameshift | 7x | n.a. | − | n.a. | n.a. | PVS1, BS2 | VUS | PM4, BS2 | VUS | LB |
4 | 1 | c.521dup | p.(Pro177fs*55) | Maternal | Frameshift | No | BAFopathy | + | +(parent−) | 1/0.13 (−/0.13) | PVS1, PM2 | LP | PS5, PM2, PM7 | LP | P |
5 | 1 | c.1029_1056del | p.(Ala349Metfs*11) | Maternal | Frameshift | No | BAFopathy | + | + | 19/0.08 | PVS1, PM2 | LP | PVS1, PS5, PM2, PM7 | P | P |
6 | 1 | c.1044_1071del | p.(Ala349Metfs*11) | Maternal | Frameshift | No | n.a. | + | + | 1/0.38 | PVS1, PM2 | LP | PVS1, PM2, PM7 | P | P |
7 | 1 | c.1044_1062del | p.(Gly351Alafs*12) | Paternal | Frameshift | No | BAFopathy | + | +(parent−) | 7/0.31 16/0.07 | PVS1, PM2 | LP | PVS1, PS5, PM2, PM7 | P | P |
8 | 3–4 | exon 3–4 deletion | p.? | Paternal | In-frame deletion | - | no BAFopathy | - | n.a. | n.a. | PM2, PM4 | VUS | PM2, PM4 | VUS | LB |
9 | 7 | c.2371+2T > C | r.spl? | Unknown | Splice site | No | n.a. | + | n.a. | n.a. | PM2, PM4, PP4 | VUS | PM2, PM4, PP4 | VUS | VUS |
10 | 8 | c.2372-2A > C | r.spl? | Maternal | Splice site | 1x | n.a. | + | n.a. | n.a. | PP4 | VUS | PP4 | VUS | VUS |
11 | 18 | c.4870C > T | p.(Arg1624*) | Father is inconclusively mosaic. Mother is negative. Siblings. | Nonsense | No | n.a. | + | n.a. | n.a. | PVS1, PM2, PP4 | P | PVS1, PM2, PP4 | P | P |
12 | 20 | c.6322C > T | p.(Gln2108*) | Paternal, mosaic father | Nonsense | No | n.a. | + | +(parent+) | 1/0.78 1/0.34 | PVS1, PM2, PP4 | P | PVS1, PM2, PM7, PP1, PP4 | P | P |
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van der Sluijs, P.J.; Alders, M.; Dingemans, A.J.M.; Parbhoo, K.; van Bon, B.W.; Dempsey, J.C.; Doherty, D.; den Dunnen, J.T.; Gerkes, E.H.; Milller, I.M.; et al. A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria. Genes 2021, 12, 1275. https://doi.org/10.3390/genes12081275
van der Sluijs PJ, Alders M, Dingemans AJM, Parbhoo K, van Bon BW, Dempsey JC, Doherty D, den Dunnen JT, Gerkes EH, Milller IM, et al. A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria. Genes. 2021; 12(8):1275. https://doi.org/10.3390/genes12081275
Chicago/Turabian Stylevan der Sluijs, Pleuntje J., Mariëlle Alders, Alexander J. M. Dingemans, Kareesma Parbhoo, Bregje W. van Bon, Jennifer C. Dempsey, Dan Doherty, Johan T. den Dunnen, Erica H. Gerkes, Ilana M. Milller, and et al. 2021. "A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria" Genes 12, no. 8: 1275. https://doi.org/10.3390/genes12081275