Heterotaxy syndrome: genetic factors (review)

Heterotaxy syndrome is usually accompanied by congenital heart defects, which predominantly determine the severity of the patient’s condition and the high mortality rate, reaching up to 80% in the first year of life. In some cases, heterotaxy is caused by chromosomal and genetic abnormalities, which have been actively studied in recent decades. According to literature data, the prevalence of pathogenic copy number variations (pCNVs) in this anomaly is estimated at 15-20%, while monogenic variants account for 10-20%. The aim of this study is to analyze the work of the past 10 years, which includes the results of genetic studies on patients with laterality disorders, and to summarize the findings to identify the most promising diagnostic methods. An electronic search was conducted using the PubMed and E-library databases, where techniques such as karyotyping, CNV determination, and exon sequencing were applied. In total, out of 1357 patients with heterotaxy who were examined by various methods in the reviewed studies, a suspected genetic cause was identified in 278 individuals, accounting for 20.5%. Karyotyping among 56 patients did not reveal any cases of aneuploidy. The search for pCNVs was conducted on 154 individuals, predominantly using array comparative genomic hybridization (aCGH), which resulted in the detection of aneuploidies in 4.5% of the subjects and pathogenic microstructural chromosomal rearrangements in 6.5%. Exome sequencing was performed on 1147 patients with heterotaxy, and pathogenic or likely pathogenic genetic variants were identified in 22.8% of cases. aCGH is considered a preferred diagnostic method due to the more severe clinical presentation of heterotaxy syndrome, which is often associated with microstructural chromosomal abnormalities, and its potential application in the prenatal stage. Exome sequencing is recommended as a second step for assessing the risk of heterotaxy recurrence in future pregnancies.

1. Seidl-Mlczoch E., Kasprian G., Ba-Ssalamah A., et al. Characterization of phenotypic spectrum of fetal heterotaxy syndrome by combining ultrasound and magnetic resonance imaging. Ultrasound Obstet Gynecol. 2021;58(6):837-845. doi:10.1002/uog.23705

2. Yi T., Sun H., Fu Y., et al. Genetic and Clinical Features of Heterotaxy in a Prenatal Cohort. Front Genet. 2022;13. doi:10.3389/fgene.2022.818241

3. Pierpont M.E., Brueckner M., Chung W.K., et al. Genetic Basis for Congenital Heart Disease: Revisited. Circulation. 2018;138(21):e653-e711. doi:10.1161/CIR.0000000000000606

4. Saba T.G., Geddes G.C., Ware S.M., et al. A multi-disciplinary, comprehensive approach to management of children with heterotaxy. Orphanet J Rare Dis. 2022;17. doi:10.1186/s13023-022-02515-2

5. Bartram U., Wirbelauer J., Speer C.P. Heterotaxy syndrome -- asplenia and polysplenia as indicators of visceral malposition and complex congenital heart disease. Biol Neonate. 2005;88(4):278-290. doi:10.1159/000087625

6. Lazarevich A.A. Sindrom geterotaksii u plodov v pervom trimestre beremennosti [Heterotaxy syndrome in fetuses in the first trimester of pregnancy]. FORCIPE. 2022;5(S2):294-295. (In Russ.)

7. Grammatikova O.A., Lutaya E.D., Goncharov G.V. Prenatal’naya diagnostika geterotaksicheskikh sindromov [Prenatal diagnosis of heterotaxy syndromes]. Prenatal’naya Diagnostika [Prenatal Diagnostics]. 2014;13(2):136-141. (In Russ.)

8. Sun H., Yi T., Hao X., et al. Contribution of single-gene defects to congenital cardiac left-sided lesions in the prenatal setting. Ultrasound Obstet Gynecol. 2020;56(2):225-232. doi:10.1002/uog.21883

9. Qin X.J., Xu M.M., Ye J.J., et al. De novo disruptive heterozygous MMP21 variants are potential predisposing genetic risk factors in Chinese Han heterotaxy children. Hum Genomics. 2022;16. doi:10.1186/s40246-022-00409-9

10. Slepukhina A.A., Lebedev I.N., Lifshitz G.I. Variatsii chisla kopiy DNK v etiologii vrozhdennykh porokov serdtsa [Variation of DNA copies number in etiology of congenital heart defects]. Rossiyskiy Kardiologicheskiy Zhurnal [Russian Journal of Cardiology]. 2018;(10):119-126. (In Russ.) https://doi.org/10.15829/1560-4071-2018-10-119-126

11. Koenig Z.A., Verhoeven A., Rosen D., Petrone A.B. Lateral Heterotaxy Syndrome in a Newborn Caucasian Male. Cureus. 12(10):e11205. doi:10.7759/cureus.11205

12. Lee M.Y., Won H.S., Shim J.Y., et al. Prenatal diagnosis of atrial isomerism in the Korean population. Obstet Gynecol Sci. 2014;57(3):193-200. doi:10.5468/ogs.2014.57.3.193

13. Ganapathi M., Buchovecky C.M., Cristo F., et al. A novel biallelic loss-of-function variant in DAND5 causes heterotaxy syndrome. Cold Spring Harb Mol Case Stud. 2022;8(7):a006248. doi:10.1101/mcs.a006248

14. Jia Y., Gao J. Bilateral inferior venae cava combined with the persistent left superior vena cava and hemiazygos continuation of left inferior vena cava with drainage into right atrium: A case report. Echocardiogr Mt Kisco N. 2023;40(7):739-742. doi:10.1111/echo.15582

15. Mastromoro G., Guadagnolo D., Novelli A., et al. Prenatal CFAP53-related laterality defect: case report and review of the literature. J Matern Fetal Neonatal Med. 2023;36(1):2201653. doi:10.1080/14767058.2023.2201653

16. Le Fevre A., Baptista J., Ellard S., et al. Compound heterozygous Pkd1l1 variants in a family with two fetuses affected by heterotaxy and complex Chd. Eur J Med Genet. 2020;63(2):103657. doi:10.1016/j.ejmg.2019.04.014

17. Buca D.I.P., Khalil A., Rizzo G., et al. Outcome of prenatally diagnosed fetal heterotaxy: systematic review and meta-analysis. Ultra-sound Obstet Gynecol. 2018;51(3):323-330. doi:10.1002/uog.17546

18. Kudryavtseva E.V., Kovalev V.V., Kanivets I.V., Kiyevskaia Yu.K., Korostelev S.A. Ispol’zovaniye khromosomnogo mikromatrichnogo analiza v prenatal’noy diagnostike v Rossii [The use of chromosomal microarray analysis in prenatal diagnosis in Russia]. Ural’skiy Meditsinskiy Zhurnal [Ural Medical Journal]. 2017;(11 (155)):12-15. (In Russ.)

19. Kievskaya J.K., Shilova N.V., Kanivets I.V., et al. Primeneniye khromosomnogo mikromatrichnogo analiza dlya diagnostiki khromosomnoy patologii u plodov s vrozhdennymi porokami serdtsa [The use of chromosomal microarray analysis for the diagnosis of chromosomal pathology in fetuses with congenital malformations of the heart]. Ural’skiy Meditsinskiy Zhurnal [Ural Medical Journal]. 2019;(15 (183)):18-22. doi:10.25694/URMJ.2019.15.06 (In Russ.)

20. Liang S., Shi X., Yu C., et al. Identification of novel candidate genes in heterotaxy syndrome patients with congenital heart diseases by whole exome sequencing. Biochim Biophys Acta BBA - Mol Basis Dis. 2020;1866(12):165906. doi:10.1016/j.bbadis.2020.165906

21. Liu S., Wei W., Wang P., et al. LOF variants identifying candidate genes of laterality defects patients with congenital heart disease. PLOS Genet. 2022;18(12):e1010530. doi:10.1371/journal.pgen.1010530

22. Ma A.C.H., Mak C.C.Y., Yeung K.S., et al. Monoallelic Mutations in CC2D1A Suggest a Novel Role in Human Heterotaxy and Ciliary Dysfunction. Circ Genomic Precis Med. 2020;13(6):e003000. doi:10.1161/CIRCGEN.120.003000

23. Deniz E., Pasha M., Guerra M.E., et al. CFAP45, a heterotaxy and congenital heart disease gene, affects cilia stability. Dev Biol. 2023;499:75-88. doi:10.1016/j.ydbio.2023.04.006

24. Li A.H., Hanchard N.A., Azamian M., et al. Genetic architecture of laterality defects revealed by whole exome sequencing. Eur J Hum Genet. 2019;27(4):563-573. doi:10.1038/s41431-018-0307-z

25. Tate G. Whole-exome sequencing reveals a combination of extremely rare single-nucleotide polymorphism of DNAH9 and RSPH1 genes in a Japanese fetus with situs viscerum inversus. Med Mol Morphol. 2021;54(3):275-280. doi:10.1007/s00795-021-00287-5

26. Li Y., Yagi H., Onuoha E.O., et al. DNAH6 and Its Interactions with PCD Genes in Heterotaxy and Primary Ciliary Dyskinesia. PLoS Genet. 2016;12(2):e1005821. doi:10.1371/journal.pgen.1005821

27. Xia H., Huang X., Deng S., et al. DNAH11 compound heterozygous variants cause heterotaxy and congenital heart disease. PLoS ONE. 2021;16(6):e0252786. doi:10.1371/journal.pone.0252786

28. Chen W., Wang F., Zeng W., et al. Biallelic mutations of TTC12 and TTC21B were identified in Chinese patients with multisystem ciliopathy syndromes. Hum Genomics. 2022;16:48. doi:10.1186/s40246-022-00421-z

29. Chen W., Zhang Y., Shen L., et al. Biallelic DNAH9 mutations are identified in Chinese patients with defective left–right patterning and ciliarelated complex congenital heart disease. Hum Genet. 2022;141(8):1339-1353. doi:10.1007/s00439-021-02426-5

30. Yue Y., Huang Q., Zhu P., et al. Identification of Pathogenic Mutations and Investigation of the NOTCH Pathway Activation in Kartagener Syndrome. Front Genet. 2019;10:749. doi:10.3389/fgene.2019.00749

31. Yuan Z.Z., Fan L.L., Jiang Z.C., Yang Y.F., Tan Z.P. A Novel Nonsense MMP21 Variant Causes Dextrocardia and Congenital Heart Disease in a Han Chinese Patient. Front Cardiovasc Med. 2020;7:582350. doi:10.3389/fcvm.2020.582350

32. Hartill V.L., van de Hoek G., Patel M.P., et al. DNAAF1 links heart laterality with the AAA+ ATPase RUVBL1 and ciliary intraflagellar transport. Hum Mol Genet. 2018;27(3):529-545. doi:10.1093/hmg/ddx422

33. Zhang Y., Chen W., Zeng W., Lu Z., Zhou X. Biallelic loss of function NEK3 mutations deacetylate α-tubulin and downregulate NUP205 that predispose individuals to ciliarelated abnormal cardiac left–right patterning. Cell Death Dis. 2020;11(11):1005. doi:10.1038/s41419-020-03214-1

34. Casey J.P., Goggin P., McDaid J., et al. A case report of primary ciliary dyskinesia, laterality defects and developmental delay caused by the co-existence of a single gene and chromosome disorder. BMC Med Genet. 2015;16:45. doi:10.1186/s12881-015-0192-z

35. Bolkier Y., Barel O., Marek-Yagel D., et al. Whole-exome sequencing reveals a monogenic cause in 56% of individuals with laterality disorders and associated congenital heart defects. J Med Genet. 2022;59(7):691-696. doi:10.1136/jmedgenet-2021-107775

36. Burkhalter M.D., Sridhar A., Sampaio P., et al. Imbalanced mitochondrial function provokes heterotaxy via aberrant ciliogenesis. J Clin Invest. 129(7):2841-2855. doi:10.1172/JCI98890

37. Breuer K., Riedhammer K.M., Müller N., et al. Exome sequencing in individuals with cardiovascular laterality defects identifies potential candidate genes. Eur J Hum Genet. 2022;30(8):946-954. doi:10.1038/s41431-022-01100-2

38. Izumi K., Noon S., Wilkens A., Krantz I.D. NKX2.5 mutation identification on exome sequencing in a patient with heterotaxy. Eur J Med Genet. 2014;57(10):558-561. doi:10.1016/j.ejmg.2014.08.003

39. Li L., Shi G., Zhang X., et al. Novel dominant-negative FOXJ1 mutation in a family with heterotaxy plus mouse model. Transl Pediatr. 2023;12(8):1476-1489. doi:10.21037/tp-23-27

40. Alsafwani R.S., Nasser K.K., Shinawi T., et al. Novel MYO1D Missense Variant Identified Through Whole Exome Sequencing and Computational Biology Analysis Expands the Spectrum of Causal Genes of Laterality Defects. Front Med. 2021;8. doi:10.3389/fmed.2021.724826

41. Guimier A., Gabriel G.C., Bajolle F., et al. MMP21 is mutated in human heterotaxy and is required for normal left-right asymmetry in vertebrates. Nat Genet. 2015;47(11):1260-1263. doi:10.1038/ng.3376

42. Suo M.J., Chen W.C., Xu Z.Q., et al. X-linked BCOR variants identified in Chinese Han patients with congenital heart disease. J Gene Med. 2023;25(1):e3461. doi:10.1002/jgm.3461

43. Perles Z., Moon S., Ta-Shma A., et al. A human laterality disorder caused by a homozygous deleterious mutation in MMP21. J Med Genet. 2015;52(12):840-847. doi:10.1136/jmedgenet-2015-103336

44. Vetrini F., D’Alessandro L.C., Akdemir Z.C., et al. Biallelic Mutations in PKD1L1 Are Associated with Laterality Defects in Humans. Am J Hum Genet. 2016;99(4):886-893. doi:10.1016/j.ajhg.2016.07.011

45. Shih J.C., Ma G.C., Cheng W.C., Chen C.Y., Wu W.J., Chen M. SMAD2 as risk locus for human left atrial isomerism detected by mother–fetus-pair exome sequencing and imaging studies. Ultrasound Obstet Gynecol. 2019;53(5):702-705. doi:10.1002/uog.19097

46. Zahid M., Bais A., Tian X., et al. Airway ciliary dysfunction and respiratory symptoms in patients with transposition of the great arteries. PLoS ONE. 2018;13(2):e0191605. doi:10.1371/journal.pone.0191605

47. Wang Y., Dai X., Liu H., Peng J., Chen J. A novel ZIC3 mutation in a Chinese family with heterotaxy and multiple types of congenital heart defect. Prenat Diagn. 2023;43(3):275-279. doi:10.1002/pd.6294

48. Marek-Yagel D., Bolkier Y., Barel O., et al. A founder truncating variant in GDF1 causes autosomal-recessive right isomerism and associated congenital heart defects in multiplex Arab kindreds. Am J Med Genet A. 2020;182(5):987-993. doi:10.1002/ajmg.a.61509

49. Karaca E., Yuregir O.O., Bozdogan S.T., et al. Rare variants in the notch signaling pathway describe a novel type of autosomal recessive Klippel-Feil syndrome. Am J Med Genet A. 2015;167A(11):2795-2799. doi:10.1002/ajmg.a.37263

50. Panchal N.K., Evan Prince S. The NEK family of serine/threonine kinases as a biomarker for cancer. Clin Exp Med. 2023;23(1):17-30. doi:10.1007/s10238-021-00782-0

51. Cao Y., Song J., Chen J., Xiao J., Ni J., Wu C. Overexpression of NEK3 is associated with poor prognosis in patients with gastric cancer. Medicine (Baltimore). 2018;97(3):e9630. doi:10.1097/MD.0000000000009630

52. Miller S.L., Antico G., Raghunath P.N., Tomaszewski J.E., Clevenger C.V. Nek3 kinase regulates prolactin-mediated cytoskeletal reorganization and motility of breast cancer cells. Oncogene. 2007;26(32):4668-4678. doi:10.1038/sj.onc.1210264

53. Suzuki K., Okuno T., Yamamoto M., et al. Semaphorin 7A initiates T-cell-mediated inflammatory responses through alpha1beta1 integrin. Nature. 2007;446(7136):680-684. doi:10.1038/nature05652

54. Gharibi A., La Kim S., Molnar J., et al. ITGA1 is a premalignant biomarker that promotes therapy resistance and metastatic potential in pancreatic cancer. Sci Rep. 2017;7(1):10060. doi:10.1038/s41598-017-09946-z

55. Yim D.H., Zhang Y.W., Eom S.Y., et al. ITGA1 polymorphisms and haplotypes are associated with gastric cancer risk in a Korean population. World J Gastroenterol. 2013;19(35):5870-5876. doi:10.3748/wjg.v19.i35.5870

56. Liu H., Zheng J., Zhu L., et al. Wdr47, Camsaps, and Katanin cooperate to generate ciliary central microtubules. Nat Commun. 2021;12(1):5796. doi:10.1038/s41467-021-26058-5

57. Chen Y., Zheng J., Li X., et al. Wdr47 Controls Neuronal Polarization through the Camsap Family Microtubule Minus-End-Binding Proteins. Cell Rep. 2020;31(3):107526. doi:10.1016/j.celrep.2020.107526

58. Ren J., Li D., Liu J., et al. Intertwined Wdr47-NTD dimer recognizes a basic-helical motif in Camsap proteins for proper central-pair microtubule formation. Cell Rep. 2022;41(6):111589. doi:10.1016/j.celrep.2022.111589

59. Gong X., Zou L., Wang M., et al. Gramicidin inhibits cholangiocarcinoma cell growth by suppressing EGR4. Artif Cells Nanomed Biotechnol. 2020;48(1):53-59. doi:10.1080/21691401.2019.1699808

60. Hogarth C.A., Mitchell D., Small C., Griswold M. EGR4 displays both a cell- and intracellular-specific localization pattern in the developing murine testis. Dev Dyn. 2010;239(11):3106-3114. doi:10.1002/dvdy.22442.

61. Mookerjee-Basu J., Hooper R., Gross S., et al. Suppression of Ca2+ signals by EGR4 controls Th1 differentiation and anticancer immunity in vivo. EMBO Rep. 2020;21(5):e48904. doi:10.15252/embr.201948904

62. Fujikawa-Adachi K., Nishimori I., Taguchi T., Onishi S. Human mitochondrial carbonic anhydrase VB. cDNA cloning, mRNA expression, subcellular localization, and mapping to chromosome x. J Biol Chem. 1999;274(30):21228-21233. doi:10.1074/jbc.274.30.21228

63. Shah G.N., Hewett-Emmett D., Grubb J.H., et al. Mitochondrial carbonic anhydrase CA VB: differences in tissue distribution and pattern of evolution from those of CA VA suggest distinct physiological roles. Proc Natl Acad Sci U S A. 2000;97(4):1677-1682. doi:10.1073/pnas.97.4.1677

64. Brenner V., Nyakatura G., Rosenthal A., Platzer M. Genomic organization of two novel genes on human Xq28: compact head to head arrangement of IDH gamma and TRAP delta is conserved in rat and mouse. Genomics. 1997;44(1):8-14. doi:10.1006/geno.1997.4822

65. Fink J.M., Dobyns W.B., Guerrini R., Hirsch B.A. Identification of a duplication of Xq28 associated with bilateral periventricular nodular heterotopia. Am J Hum Genet. 1997;61(2):379-387. doi:10.1086/514863

66. Zhu S., Wang W., Zhang J., Ji S., Jing Z., Chen Y.Q. Slc25a5 regulates adipogenesis by modulating ERK signaling in OP9 cells. Cell Mol Biol Lett. 2022;27(1):11. doi:10.1186/s11658-022-00314-y

67. Chen Y.J., Hong W.F., Liu M.L., et al. An integrated bioinformatic investigation of mitochondrial solute carrier family 25 (SLC25) in colon cancer followed by preliminary validation of member 5 (SLC25A5) in tumorigenesis. Cell Death Dis. 2022;13(3):237. doi:10.1038/s41419-022-04692-1

68. Palmieri F. The mitochondrial transporter family SLC25: identification, properties and physiopathology. Mol Aspects Med. 2013;34(2-3):465-484. doi:10.1016/j.mam.2012.05.005

69. Bauer M.F., Gempel K., Reichert A.S., et al. Genetic and structural characterization of the human mitochondrial inner membrane translocase. J Mol Biol. 1999;289(1):69-82. doi:10.1006/jmbi.1999.2751

70. Mingting Duan, Yun Ren, Jiwen Zhang, Tingting Zhang, Yanhong Wang, Hongyan Jia. High Expression of TIMM17B Is a Potential Diagnostic and Prognostic Marker of Breast Cancer. Cell Mol Biol (Noisyle-grand). 2023;69(3):169-176. doi:10.14715/cmb/2023.69.3.25

71. Serra K.M., Vyzas C., Shehreen S., et al. Vertebral pattern and morphology is determined during embryonic segmentation [published online ahead of print, 2023 Sep 9]. Dev Dyn. 2023;10.1002/dvdy.649. doi:10.1002/dvdy.649

72. Yabe T., Uriu K., Takada S. Ripply suppresses Tbx6 to induce dynamic-to-static conversion in somite segmentation. Nat Commun. 2023;14(1):2115. doi:10.1038/s41467-023-37745-w

73. Kinoshita H., Ohgane N., Fujino Y., et al. Functional roles of the Ripply-mediated suppression of segmentation gene expression at the anterior presomitic mesoderm in zebrafish. Mech Dev. 2018; 152: 21-31. doi:10.1016/j.mod.2018.06.001

74. Walpole S.M., Hiriyana K.T., Nicolaou A., et al. Identification and characterization of the human homologue (RAI2) of a mouse retinoic acid-induced gene in Xp22. Genomics. 1999;55(3):275-283. doi:10.1006/geno.1998.5667

75. Nishikawa S., Uemoto Y., Kim T.S., et al. Low RAI2 expression is a marker of poor prognosis in breast cancer. Breast Cancer Res Treat. 2021;187(1):81-93. doi:10.1007/s10549-021-06176-w

76. Zhang W., Kong L., Zhu H., et al. Retinoic Acid-Induced 2 (RAI2) Is a Novel Antagonist of Wnt/β-Catenin Signaling Pathway and Potential Biomarker of Chemosensitivity in Colorectal Cancer. Front Oncol. 2022;12:805290. doi:10.3389/fonc.2022.805290

77. Galang G., Mandla R., Ruan H., et al. ATAC-Seq Reveals an Isl1 Enhancer That Regulates Sinoatrial Node Development and Function. Circ Res. 2020;127(12):1502-1518. doi:10.1161/CIRCRESAHA.120.317145

78. Bu L., Jiang X., Martin-Puig S., et al. Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature. 2009;460(7251):113-117. doi:10.1038/nature08191

79. Ren J., Miao D., Li Y., Gao R. Spotlight on Isl1: A Key Player in Cardiovascular Development and Diseases. Front Cell Dev Biol. 2021;9:793605. doi:10.3389/fcell.2021.793605

80. Wang K., Zhao S., Liu B., et al. Perturbations of BMP/TGF-β and VEGF/VEGFR signalling pathways in non-syndromic sporadic brain arteriovenous malformations (BAVM). J Med Genet. 2018;55(10):675-684. doi:10.1136/jmedgenet-2017-105224

81. Zhao X., Li D., Qiu Q., et al. Zfyve16 regulates the proliferation of B-lymphoid cells. Front Med. 2018;12(5):559-565. doi:10.1007/s11684-017-0562-3

82. Cheong A., Lingutla R., Mager J. Expression analysis of mammalian mitochondrial ribosomal protein genes. Gene Expr Patterns. 2020;38:119147. doi:10.1016/j.gep.2020.119147

83. Sultana N., Rahman M., Myti S., Islam J., Mustafa M.G., Nag K. A novel knowledge-derived data potentizing method revealed unique liver cancer-associated genetic variants. Hum Genomics. 2019;13(1):30. doi:10.1186/s40246-019-0213-7

84. Fakhro K.A., Choi M., Ware S.M., et al. Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning. Proc Natl Acad Sci U S A. 2011;108(7):2915-2920. doi:10.1073/pnas.1019645108

85. Spéder P., Adám G., Noselli S. Type ID unconventional myosin controls left-right asymmetry in Drosophila. Nature. 2006;440(7085):803-807. doi:10.1038/nature04623

86. Hozumi S., Maeda R., Taniguchi K., et al. An unconventional myosin in Drosophila reverses the default handedness in visceral organs. Nature. 2006;440(7085):798-802. doi:10.1038/nature04625