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| Differences in sex development v4.22 | TBX6 |
Luke Stuart gene: TBX6 was added gene: TBX6 was added to Differences in sex development. Sources: Literature Mode of inheritance for gene: TBX6 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: TBX6 were set to 36049007; 23954021 Phenotypes for gene: TBX6 were set to Mullerian aplasia (MONDO:0019128); Mayer-Rokitansky-Kuster-Hauser syndrome (MONDO:0017771) Review for gene: TBX6 was set to AMBER Added comment: Ma et al. 2022 (PMID 36049007): 622 Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) probands, 16 rare heterozygous TBX6 variants, all single alleles with no biallelic or in-trans genotypes. Several variants were supported by in vitro functional evidence (splice/frameshift c.423G>A p.Leu141Leu, c.839+5G>A; reduced protein c.422T>C p.Leu141Pro, c.745G>A Val249Met; reduced transactivation c.10C>T, c.400G>A; mislocalisation c.356G>A p.Arg119His plus one prior canonical splice variant c.621+1G>A. Against diagnostic-grade rating: segregation studies showed multiple non manifesting female carriers suggesting incomplete penetrance (unaffected carrier mother, c.10C>T p.Pro4Ser; two of three carrier sisters with normal uterus, c.356G>A p.Arg119His), penetrance of the Müllerian phenotype is low among TBX6 LoF and 16p11.2-deletion carriers generally, and no second in-trans allele was found. The authors propose an digenic/oligogenic model in which TBX6 confers risk of urogenital phenotypes. No family showed penetrant monogenic segregation. Sandbacka et al. 2013 (PMID 23954021): ascertained series of 112 mullerain aplasia (MA) patients vs 200 controls. Heterozygous whole-gene TBX6/16p11.2 deletion in 5/112, three of whom also had skeletal/vertebral findings; this recurrent deletion is found in unaffected and non-reproductive-phenotype carriers elsewhere, indicating low penetrance of this phenotype. Splice variant c.622-2A>T in two patients was predicted LoF but RT-PCR was inconclusive. Two recurrent missense variants (p.Gly162Ser, p.Arg272Gln) were enriched in affecteds but also frequent in controls. No segregation data was shown. Two patients were homozygous for both recurrent TBX6 missense variants (p.Gly162Ser, p.Arg272Gln): one also carried a heterozygous missense variant in LHX1 (p.Pro312His), another a candidate gene for MRKHS, the other an 11q13.4 deletion. A third patient, heterozygous for both TBX6 recurrent missense variants, also carried LHX1 p.Pro312His. Overall: both studies support risk association and complex/oligogenic inheritance, but neither provides segregation, completed functional validation of a penetrant effect, or convincing evidence free of confounding co-occurring variants. The evidence does not meet criteria for penetrant monogenic disease reportable in a diagnostic setting; amber rating is appropriate. This phenotype regarding TBX6 is not cited in OMIM. Sources: Literature |
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