Clinical Features and Genetic Analysis of a Case Series of Skeletal Ciliopathies in a Prenatal Setting

Overview

Journal BMC Med Genomics

Publisher Biomed Central

Specialty Genetics

Date 2023 Dec 7

PMID 38062428

Authors

Ying Peng

Lin Zhou

Jing Chen

Xiaoliang Huang

Jialun Pang

Jing Liu

Wanglan Tang

Shuting Yang

Changbiao Liang

Wanqin Xie

Affiliations

Soon will be listed here.

Abstract

Background: Short-rib polydactyly syndrome (SRPS) refers to a group of lethal skeletal dysplasias that can be difficult to differentiate between subtypes or from other non-lethal skeletal dysplasias such as Ellis-van Creveld syndrome and Jeune syndrome in a prenatal setting. We report the ultrasound and genetic findings of four unrelated fetuses with skeletal dysplasias.

Methods: Systemic prenatal ultrasound examination was performed in the second or third trimester. Genetic tests including GTG-banding, single nucleotide polymorphism (SNP) array and exome sequencing were performed with amniocytes or aborted fetal tissues.

Results: The major and common ultrasound anomalies for the four unrelated fetuses included short long bones of the limbs and narrow thorax. No chromosomal abnormalities and pathogenic copy number variations were detected. Exome sequencing revealed three novel variants in the DYNC2H1 gene, namely NM_001080463.2:c.6809G > A p.(Arg2270Gln), NM_001080463.2:3133C > T p.(Gln1045Ter), and NM_001080463.2:c.337C > T p.(Arg113Trp); one novel variant in the IFT172 gene, NM_015662.3:4540-5 T > A; and one novel variant in the WDR19 gene, NM_025132.4:c.2596G > C p.(Gly866Arg). The genotypes of DYNC2H1, IFT172 and WDR19 and the phenotypes of the fetuses give hints for the diagnosis of short-rib thoracic dysplasia (SRTD) with or without polydactyly 3, 10, and 5, respectively.

Conclusion: Our findings expand the mutation spectrum of DYNC2H1, IFT172 and WDR19 associated with skeletal ciliopathies, and provide useful information for prenatal diagnosis and genetic counseling on rare skeletal disorders.

References

Westerfield L, Stover S, Mathur V, Nassef S, Carter T, Yang Y . Reproductive genetic counseling challenges associated with diagnostic exome sequencing in a large academic private reproductive genetic counseling practice. Prenat Diagn. 2015; 35(10):1022-9. DOI: 10.1002/pd.4674. View

Schaefer E, Stoetzel C, Scheidecker S, Geoffroy V, Prasad M, Redin C . Identification of a novel mutation confirms the implication of IFT172 (BBS20) in Bardet-Biedl syndrome. J Hum Genet. 2016; 61(5):447-50. DOI: 10.1038/jhg.2015.162. View

Thiel C, Kessler K, Giessl A, Dimmler A, Shalev S, von der Haar S . NEK1 mutations cause short-rib polydactyly syndrome type majewski. Am J Hum Genet. 2011; 88(1):106-14. PMC: 3014367. DOI: 10.1016/j.ajhg.2010.12.004. View

Bredrup C, Saunier S, Oud M, Fiskerstrand T, Hoischen A, Brackman D . Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19. Am J Hum Genet. 2011; 89(5):634-43. PMC: 3213394. DOI: 10.1016/j.ajhg.2011.10.001. View

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5):405-24. PMC: 4544753. DOI: 10.1038/gim.2015.30. View

Alfadhel M, Umair M, Almuzzaini B, Alsaif S, AlMohaimeed S, Almashary M . Targeted SLC19A3 gene sequencing of 3000 Saudi newborn: a pilot study toward newborn screening. Ann Clin Transl Neurol. 2019; 6(10):2097-2103. PMC: 6801173. DOI: 10.1002/acn3.50898. View

Fehrenbach H, Decker C, Eisenberger T, Frank V, Hampel T, Walden U . Mutations in WDR19 encoding the intraflagellar transport component IFT144 cause a broad spectrum of ciliopathies. Pediatr Nephrol. 2014; 29(8):1451-6. DOI: 10.1007/s00467-014-2762-2. View

Peng Y, Yang S, Huang X, Pang J, Liu J, Hu J . Whole Exome Sequencing Analysis in Fetal Skeletal Dysplasia Detected by Ultrasonography: An Analysis of 38 Cases. Front Genet. 2021; 12:728544. PMC: 8461062. DOI: 10.3389/fgene.2021.728544. View

Ni X, Wang J, Lv M, Liu C, Zhong Y, Tian S . A novel homozygous mutation in WDR19 induces disorganization of microtubules in sperm flagella and nonsyndromic asthenoteratospermia. J Assist Reprod Genet. 2020; 37(6):1431-1439. PMC: 7311615. DOI: 10.1007/s10815-020-01770-1. View

10.

Daoud H, Luco S, Li R, Bareke E, Beaulieu C, Jarinova O . Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit. CMAJ. 2016; 188(11):E254-E260. PMC: 4978597. DOI: 10.1503/cmaj.150823. View

11.

Dagoneau N, Goulet M, Genevieve D, Sznajer Y, Martinovic J, Smithson S . DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III. Am J Hum Genet. 2009; 84(5):706-11. PMC: 2681009. DOI: 10.1016/j.ajhg.2009.04.016. View

12.

Tsurumi Y, Hamada Y, Katoh Y, Nakayama K . Interactions of the dynein-2 intermediate chain WDR34 with the light chains are required for ciliary retrograde protein trafficking. Mol Biol Cell. 2019; 30(5):658-670. PMC: 6589695. DOI: 10.1091/mbc.E18-10-0678. View

13.

Eleftheriades M, Iavazzo C, Manolakos E, Hassiakos D, Botsis D, Petersen M . Recurrent short rib polydactyly syndrome. J Obstet Gynaecol. 2012; 33(1):14-6. DOI: 10.3109/01443615.2012.698334. View

14.

Schmidts M . Clinical genetics and pathobiology of ciliary chondrodysplasias. J Pediatr Genet. 2014; 3(2):46-94. PMC: 4262788. DOI: 10.3233/PGE-14089. View

15.

Chen C, Ko T, Chang T, Chern S, Chen S, Lai S . Prenatal diagnosis of short-rib polydactyly syndrome type III or short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3) associated with compound heterozygous mutations in DYNC2H1 in a fetus. Taiwan J Obstet Gynecol. 2018; 57(1):123-127. DOI: 10.1016/j.tjog.2017.12.021. View

16.

Mortier G, Cohn D, Cormier-Daire V, Hall C, Krakow D, Mundlos S . Nosology and classification of genetic skeletal disorders: 2019 revision. Am J Med Genet A. 2019; 179(12):2393-2419. DOI: 10.1002/ajmg.a.61366. View

17.

Halbritter J, Porath J, Diaz K, Braun D, Kohl S, Chaki M . Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. Hum Genet. 2013; 132(8):865-84. PMC: 4643834. DOI: 10.1007/s00439-013-1297-0. View

18.

Liem Jr K, Ashe A, He M, Satir P, Moran J, Beier D . The IFT-A complex regulates Shh signaling through cilia structure and membrane protein trafficking. J Cell Biol. 2012; 197(6):789-800. PMC: 3373400. DOI: 10.1083/jcb.201110049. View

19.

Alyafee Y, Al Tuwaijri A, Alam Q, Umair M, Haddad S, Alharbi M . Next Generation Sequencing Based Non-invasive Prenatal Testing (NIPT): First Report From Saudi Arabia. Front Genet. 2021; 12:630787. PMC: 7889598. DOI: 10.3389/fgene.2021.630787. View

20.

Bujakowska K, Zhang Q, Siemiatkowska A, Liu Q, Place E, Falk M . Mutations in IFT172 cause isolated retinal degeneration and Bardet-Biedl syndrome. Hum Mol Genet. 2014; 24(1):230-42. PMC: 4326328. DOI: 10.1093/hmg/ddu441. View