Androgen Insensitivity Syndrome DUE to Non-Coding Variation in the Androgen Receptor Gene: Review of the Literature and Case Report of a Patient with Mosaic c.-547C>T Variant

1. Kyriakou A, Lucas-Herald AK, McGowan R, Tobias ES, and Ahmed SF. Disorders of sex development: advances in genetic diagnosis and challenges in management. Advances in Genomics and Genetics. 2015; 5: 165–177. KyriakouA Lucas-HeraldAK McGowanR TobiasES AhmedSF Disorders of sex development: advances in genetic diagnosis and challenges in management Advances in Genomics and Genetics 2015 5 165 177 Search in Google Scholar

2. Eggers S, Sadedin S, van den Bergen JA, Robevska G, Ohnesorg T, Hewitt J, et al. Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. Genome Biol. 2016; 17(1): 243. EggersS SadedinS van den BergenJA RobevskaG OhnesorgT HewittJ Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort Genome Biol 2016 17 1 243 Search in Google Scholar

3. Batista RL, Costa EMF, Rodrigues AS, Gomes NL, Faria JA, Jr., Nishi MY, et al. Androgen insensitivity syndrome: a review. Arch Endocrinol Metab. 2018; 62(2): 227–235. BatistaRL CostaEMF RodriguesAS GomesNL FariaJAJr. NishiMY Androgen insensitivity syndrome: a review Arch Endocrinol Metab 2018 62 2 227 235 Search in Google Scholar

4. Boehmer AL, Brinkmann O, Brüggenwirth H, van Assendelft C, Otten BJ, Verleun-Mooijman MC, et al. Genotype versus phenotype in families with androgen insensitivity syndrome. J Clin Endocrinol Metab. 2001; 86(9): 4151–60. BoehmerAL BrinkmannO BrüggenwirthH van AssendelftC OttenBJ Verleun-MooijmanMC Genotype versus phenotype in families with androgen insensitivity syndrome J Clin Endocrinol Metab 2001 86 9 4151 60 Search in Google Scholar

5. Gottlieb B, Beitel LK, Nadarajah A, Paliouras M, and Trifiro M. The androgen receptor gene mutations database: 2012 update. Hum Mutat. 2012; 33(5): 887–94. GottliebB BeitelLK NadarajahA PaliourasM TrifiroM The androgen receptor gene mutations database: 2012 update Hum Mutat 2012 33 5 887 94 Search in Google Scholar

6. Camats N, Flück CE, and Audí L. Oligogenic Origin of Differences of Sex Development in Humans. Int J Mol Sci. 2020; 21(5). CamatsN FlückCE AudíL Oligogenic Origin of Differences of Sex Development in Humans Int J Mol Sci 2020 21 5 Search in Google Scholar

7. Boehmer AL, Brinkmann AO, Nijman RM, Verleun-Mooijman MC, de Ruiter P, Niermeijer MF, et al. Phenotypic variation in a family with partial androgen insensitivity syndrome explained by differences in 5alpha dihydrotestosterone availability. J Clin Endocrinol Metab. 2001; 86(3): 1240–6. BoehmerAL BrinkmannAO NijmanRM Verleun-MooijmanMC de RuiterP NiermeijerMF Phenotypic variation in a family with partial androgen insensitivity syndrome explained by differences in 5alpha dihydrotestosterone availability J Clin Endocrinol Metab 2001 86 3 1240 6 Search in Google Scholar

8. Köhler B, Lumbroso S, Leger J, Audran F, Grau ES, Kurtz F, et al. Androgen insensitivity syndrome: somatic mosaicism of the androgen receptor in seven families and consequences for sex assignment and genetic counseling. J Clin Endocrinol Metab. 2005; 90(1): 106–11. KöhlerB LumbrosoS LegerJ AudranF GrauES KurtzF Androgen insensitivity syndrome: somatic mosaicism of the androgen receptor in seven families and consequences for sex assignment and genetic counseling J Clin Endocrinol Metab 2005 90 1 106 11 Search in Google Scholar

9. Hornig NC, de Beaufort C, Denzer F, Cools M, Wabitsch M, Ukat M, et al. A Recurrent Germline Mutation in the 5′UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation. Plos one. 2016; 11(4): e0154158. HornigNC de BeaufortC DenzerF CoolsM WabitschM UkatM A Recurrent Germline Mutation in the 5′UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation Plos one 2016 11 4 e0154158 Search in Google Scholar

10. Noveski P, Terzic M, Vujovic M, Kuzmanovska M, Sukarova Stefanovska E, and Plaseska-Karanfilska D. Multilevel regression modeling for aneuploidy classification and physical separation of maternal cell contamination facilitates the QF-PCR based analysis of common fetal aneuploidies. Plos one. 2019; 14(8): e0221227. NoveskiP TerzicM VujovicM KuzmanovskaM Sukarova StefanovskaE Plaseska-KaranfilskaD Multilevel regression modeling for aneuploidy classification and physical separation of maternal cell contamination facilitates the QF-PCR based analysis of common fetal aneuploidies Plos one 2019 14 8 e0221227 Search in Google Scholar

11. Plaseski T, Noveski P, Trivodalieva S, Efremov GD, and Plaseska-Karanfilska D. Quantitative fluorescent-PCR detection of sex chromosome aneuploidies and AZF deletions/duplications. Genetic testing. 2008; 12(4): 595–605. PlaseskiT NoveskiP TrivodalievaS EfremovGD Plaseska-KaranfilskaD Quantitative fluorescent-PCR detection of sex chromosome aneuploidies and AZF deletions/duplications Genetic testing 2008 12 4 595 605 Search in Google Scholar

12. Noveski P, Madjunkova S, Sukarova Stefanovska E, Matevska Geshkovska N, Kuzmanovska M, Dimovski A, et al. Loss of Y chromosome in peripheral blood of colorectal and prostate cancer patients. Plos one. 2016; 11(1): e0146264. NoveskiP MadjunkovaS Sukarova StefanovskaE Matevska GeshkovskaN KuzmanovskaM DimovskiA Loss of Y chromosome in peripheral blood of colorectal and prostate cancer patients Plos one 2016 11 1 e0146264 Search in Google Scholar

13. Zhang X, Wakeling M, Ware J, and Whiffin N. Annotating high-impact 5′untranslated region variants with the UTRannotator. Bioinformatics. 2021; 37(8): 1171–1173. ZhangX WakelingM WareJ WhiffinN Annotating high-impact 5′untranslated region variants with the UTRannotator Bioinformatics 2021 37 8 1171 1173 Search in Google Scholar

14. McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, et al. The Ensembl Variant Effect Predictor. Genome Biol. 2016; 17(1): 122. McLarenW GilL HuntSE RiatHS RitchieGR ThormannA The Ensembl Variant Effect Predictor Genome Biol 2016 17 1 122 Search in Google Scholar

15. Baetens D, Mendonça BB, Verdin H, Cools M, and De Baere E. Non-coding variation in disorders of sex development. Clin Genet. 2017; 91(2): 163–172. BaetensD MendonçaBB VerdinH CoolsM De BaereE Non-coding variation in disorders of sex development Clin Genet 2017 91 2 163 172 Search in Google Scholar

16. Soukarieh O, Meguerditchian C, Proust C, Aïssi D, Eyries M, Goyenvalle A, et al. Common and Rare 5′UTR Variants Altering Upstream Open Reading Frames in Cardiovascular Genomics. Front Cardiovasc Med. 2022; 9: 841032. SoukariehO MeguerditchianC ProustC AïssiD EyriesM GoyenvalleA Common and Rare 5′UTR Variants Altering Upstream Open Reading Frames in Cardiovascular Genomics Front Cardiovasc Med 2022 9 841032 Search in Google Scholar

17. Whiffin N, Karczewski KJ, Zhang X, Chothani S, Smith MJ, Evans DG, et al. Characterising the loss-of-function impact of 5′ untranslated region variants in 15,708 individuals. Nat Commun. 2020; 11(1): 2523. WhiffinN KarczewskiKJ ZhangX ChothaniS SmithMJ EvansDG Characterising the loss-of-function impact of 5′ untranslated region variants in 15,708 individuals Nat Commun 2020 11 1 2523 Search in Google Scholar

18. Calvo SE, Pagliarini DJ, and Mootha VK. Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. Proc Natl Acad Sci U S A. 2009; 106(18): 7507–12. CalvoSE PagliariniDJ MoothaVK Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans Proc Natl Acad Sci U S A 2009 106 18 7507 12 Search in Google Scholar

19. Lee DSM, Park J, Kromer A, Baras A, Rader DJ, Ritchie MD, et al. Disrupting upstream translation in mRNAs is associated with human disease. Nat Commun. 2021; 12(1): 1515. LeeDSM ParkJ KromerA BarasA RaderDJ RitchieMD Disrupting upstream translation in mRNAs is associated with human disease Nat Commun 2021 12 1 1515 Search in Google Scholar

20. Chen S, Francioli LC, Goodrich JK, Collins RL, Kanai M, Wang Q, et al. A genome-wide mutational constraint map quantified from variation in 76,156 human genomes. bioRxiv. 2022: 2022.03.20.485034. ChenS FrancioliLC GoodrichJK CollinsRL KanaiM WangQ A genome-wide mutational constraint map quantified from variation in 76,156 human genomes bioRxiv 2022 2022.03.20.485034 Search in Google Scholar

21. Holterhus PM, Brüggenwirth HT, Hiort O, Kleinkauf-Houcken A, Kruse K, Sinnecker GH, et al. Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome. J Clin Endocrinol Metab. 1997; 82(11): 3584–9. HolterhusPM BrüggenwirthHT HiortO Kleinkauf-HouckenA KruseK SinneckerGH Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome J Clin Endocrinol Metab 1997 82 11 3584 9 Search in Google Scholar

22. Gottlieb B and Trifiro MA. Androgen Insensitivity Syndrome [Updated 2017 May 11]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1429/. 1993. GottliebB TrifiroMA Androgen Insensitivity Syndrome [Updated 2017 May 11] In: AdamMP MirzaaGM PagonRA editors. GeneReviews® [Internet] Seattle (WA) University of Washington, Seattle 1993 2023 Available from: https://www.ncbi.nlm.nih.gov/books/NBK1429/ 1993 Search in Google Scholar

23. Batista RL, Yamaguchi K, Rodrigues ADS, Nishi MY, Goodier JL, Carvalho LR, et al. Mobile DNA in Endocrinology: LINE-1 Retrotransposon Causing Partial Androgen Insensitivity Syndrome. J Clin Endocrinol Metab. 2019; 104(12): 6385–6390. BatistaRL YamaguchiK RodriguesADS NishiMY GoodierJL CarvalhoLR Mobile DNA in Endocrinology: LINE-1 Retrotransposon Causing Partial Androgen Insensitivity Syndrome J Clin Endocrinol Metab 2019 104 12 6385 6390 Search in Google Scholar

24. Ono H, Saitsu H, Horikawa R, Nakashima S, Ohkubo Y, Yanagi K, et al. Partial androgen insensitivity syndrome caused by a deep intronic mutation creating an alternative splice acceptor site of the AR gene. Sci Rep. 2018; 8(1): 2287. OnoH SaitsuH HorikawaR NakashimaS OhkuboY YanagiK Partial androgen insensitivity syndrome caused by a deep intronic mutation creating an alternative splice acceptor site of the AR gene Sci Rep 2018 8 1 2287 Search in Google Scholar

25. Kalinchenko NY, Petrov VM, Panova AV, and Tiulpakov AN. [A deep intronic mutation in AR gene causing androgen insensitivity syndrome: difficulties of diagnostics]. Probl Endokrinol (Mosk). 2021; 67(5): 48–52. KalinchenkoNY PetrovVM PanovaAV TiulpakovAN [A deep intronic mutation in AR gene causing androgen insensitivity syndrome: difficulties of diagnostics] Probl Endokrinol (Mosk) 2021 67 5 48 52 Search in Google Scholar

26. Brüggenwirth HT, Boehmer AL, Ramnarain S, Verleun-Mooijman MC, Satijn DP, Trapman J, et al. Molecular analysis of the androgen-receptor gene in a family with receptor-positive partial androgen insensitivity: an unusual type of intronic mutation. Am J Hum Genet. 1997; 61(5): 1067–77. BrüggenwirthHT BoehmerAL RamnarainS Verleun-MooijmanMC SatijnDP TrapmanJ Molecular analysis of the androgen-receptor gene in a family with receptor-positive partial androgen insensitivity: an unusual type of intronic mutation Am J Hum Genet 1997 61 5 1067 77 Search in Google Scholar

27. Känsäkoski J, Jääskeläinen J, Jääskeläinen T, Tommiska J, Saarinen L, Lehtonen R, et al. Complete androgen insensitivity syndrome caused by a deep intronic pseudoexon-activating mutation in the androgen receptor gene. Sci Rep. 2016; 6: 32819. KänsäkoskiJ JääskeläinenJ JääskeläinenT TommiskaJ SaarinenL LehtonenR Complete androgen insensitivity syndrome caused by a deep intronic pseudoexon-activating mutation in the androgen receptor gene Sci Rep 2016 6 32819 Search in Google Scholar

28. Miller DE, Lee L, Galey M, Kandhaya-Pillai R, Tischkowitz M, Amalnath D, et al. Targeted long-read sequencing identifies missing pathogenic variants in unsolved Werner syndrome cases. J Med Genet. 2022; 59(11): 1087–94. MillerDE LeeL GaleyM Kandhaya-PillaiR TischkowitzM AmalnathD Targeted long-read sequencing identifies missing pathogenic variants in unsolved Werner syndrome cases J Med Genet 2022 59 11 1087 94 Search in Google Scholar

29. Miller DE, Sulovari A, Wang T, Loucks H, Hoekzema K, Munson KM, et al. Targeted long-read sequencing identifies missing disease-causing variation. Am J Hum Genet. 2021; 108(8): 1436–1449. MillerDE SulovariA WangT LoucksH HoekzemaK MunsonKM Targeted long-read sequencing identifies missing disease-causing variation Am J Hum Genet 2021 108 8 1436 1449 Search in Google Scholar