Evaluation of evidence for pathogenicity demonstrates that<i>BLK, KLF11</i>and<i>PAX4</i>should not be included in diagnostic testing for MODY
Abstract Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant form of monogenic diabetes, reported to be caused by variants in 16 genes. Concern has been raised about whether variants inBLK(MODY11),KLF11(MODY7) andPAX4(MODY9) cause MODY. We examined variant-level genetic evidence (co-segregation with diabetes and frequency in population) for published putative pathogenic variants in these genes and used burden testing to test gene-level evidence in a MODY cohort (n=1227) compared to population control (UK Biobank, n=185,898). For comparison we analysed well-established causes of MODY,HNF1AandHNF4A. The published variants inBLK, KLF11andPAX4showed poor co-segregation with diabetes (combined LOD scores ≤1.2), compared toHNF1AandHNF4A(LOD scores >9), and are all too common to cause MODY (minor allele frequency >4.95×10−5). Ultra-rare missense and protein-truncating variants (PTVs) were not enriched in a MODY cohort compared to the UK Biobank (PTVsP>0.05, missenseP>0.1 for all three genes) whileHNF1AandHNF4Awere enriched (P<10−6). Sensitivity analyses using different population cohorts supported our results. Variant and gene-level genetic evidence does not supportBLK, KLF11orPAX4as causes of MODY. They should not be included in MODY diagnostic genetic testing..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 09. Jan. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Laver, Thomas W [VerfasserIn] |
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| doi: |
10.1101/2021.09.17.21263728 |
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| PPN (Katalog-ID): |
XBI032634552 |
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| 245 | 1 | 0 | |a Evaluation of evidence for pathogenicity demonstrates that<i>BLK, KLF11</i>and<i>PAX4</i>should not be included in diagnostic testing for MODY |
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| 520 | |a Abstract Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant form of monogenic diabetes, reported to be caused by variants in 16 genes. Concern has been raised about whether variants inBLK(MODY11),KLF11(MODY7) andPAX4(MODY9) cause MODY. We examined variant-level genetic evidence (co-segregation with diabetes and frequency in population) for published putative pathogenic variants in these genes and used burden testing to test gene-level evidence in a MODY cohort (n=1227) compared to population control (UK Biobank, n=185,898). For comparison we analysed well-established causes of MODY,HNF1AandHNF4A. The published variants inBLK, KLF11andPAX4showed poor co-segregation with diabetes (combined LOD scores ≤1.2), compared toHNF1AandHNF4A(LOD scores >9), and are all too common to cause MODY (minor allele frequency >4.95×10−5). Ultra-rare missense and protein-truncating variants (PTVs) were not enriched in a MODY cohort compared to the UK Biobank (PTVsP>0.05, missenseP>0.1 for all three genes) whileHNF1AandHNF4Awere enriched (P<10−6). Sensitivity analyses using different population cohorts supported our results. Variant and gene-level genetic evidence does not supportBLK, KLF11orPAX4as causes of MODY. They should not be included in MODY diagnostic genetic testing. | ||
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| 700 | 1 | |a Knox, Olivia |4 aut | |
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