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Chen W, Li Y, Zhang J, Yuan Y, Sun D, Yuan J, Yang K, Liang Y, Guo Q. Genetic variations in the DYNC2H1 gene causing SRTD3 (short-rib thoracic dysplasia 3 with or without polydactyly). Front Genet 2023; 14:1125473. [PMID: 37091781 PMCID: PMC10116042 DOI: 10.3389/fgene.2023.1125473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 03/27/2023] [Indexed: 04/25/2023] Open
Abstract
Background and aims: Short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3) represents a type of severe fetal skeletal dysplasia (SD) characterized by shortened limbs, narrow thorax with or without polydactyly, which is caused by the homozygous or compound heterozygous mutations in the DYNC2H1 gene. SRTD3 is a recessive disorder, identification of the responsible genetic variation would be beneficial to an accurate prenatal diagnosis and well-grounded counseling for the affected families. Material and methods: Two families having experienced recurrent fetal SDs were recruited and submitted to a multiplatform genetic investigation. Whole-exome sequencing (WES) was performed with samples collected from the probands. Sanger sequencing and fluorescent quantitative PCR (qPCR) were conducted as validation assays for suspected variations. Results: WES identified two compound heterozygous variations in the DYNC2H1(NM_001080463.2) gene, namely c.2386C>T (p.Arg796Trp) and c.7289T>C (p.Ile2430Thr) for one; and exon (64-83)del and c.8190G>T (p.Leu2730Phe) for the other, respectively. One variant in them, exon (64-83)del, was novelly identified. Conclusion: The study detected two compound heterozygous variation in DYNC2H1 including one novel deletion: exon (64-83) del. Our findings clarified the cause of fetal skeletal dysplasia in the subject families, provided guidance for their future pregnancies, and highlighted the value of WES in diagnosis of skeletal dysplasia with unclear prenatal indications.
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Affiliation(s)
- Wenqi Chen
- Prenatal Diagnosis Center, Shijiazhuang Obstetrics and Gynecology Hospital, Key Laboratory of Maternal and Fetal Medicine of Hebei Province, Shijiazhuang, Hebei, China
| | - Yazhou Li
- Department of Pediatric Orthopaedic, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jing Zhang
- Prenatal Diagnosis Center, Shijiazhuang Obstetrics and Gynecology Hospital, Key Laboratory of Maternal and Fetal Medicine of Hebei Province, Shijiazhuang, Hebei, China
| | - Yufan Yuan
- Prenatal Diagnosis Center, Shijiazhuang Obstetrics and Gynecology Hospital, Key Laboratory of Maternal and Fetal Medicine of Hebei Province, Shijiazhuang, Hebei, China
| | - Donglan Sun
- Prenatal Diagnosis Center, Shijiazhuang Obstetrics and Gynecology Hospital, Key Laboratory of Maternal and Fetal Medicine of Hebei Province, Shijiazhuang, Hebei, China
| | - Jiayu Yuan
- Department of Pediatric Orthopaedic, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Kai Yang
- Prenatal Diagnosis Center, Beijing Obstetrics and Gynecology Hospital, Beijing Maternal and Child Healthcare Hospital, Capital Medical University, Beijing, China
| | - Ying Liang
- Reproductive Medicine Center, Shijiazhuang Obstetrics and Gynecology Hospital, Shijiazhuang, Hebei, China
- *Correspondence: Qing Guo, ; Ying Liang,
| | - Qing Guo
- Prenatal Diagnosis Center, Shijiazhuang Obstetrics and Gynecology Hospital, Key Laboratory of Maternal and Fetal Medicine of Hebei Province, Shijiazhuang, Hebei, China
- *Correspondence: Qing Guo, ; Ying Liang,
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Chen CP, Ko TM, Chang TY, Chern SR, Chen SW, Lai ST, Chuang TY, Wang W. 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; 57:123-127. [PMID: 29458881 DOI: 10.1016/j.tjog.2017.12.021] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/04/2017] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVE We present the perinatal imaging findings and molecular genetic analysis in a fetus with short-rib polydactyly syndrome (SRPS) type III or short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3). CASE REPORT A 29-year-old, primigravid woman was referred for genetic counseling at 15 weeks of gestation because of abnormal ultrasound findings of short limbs, a narrow chest and bilateral polydactyly of the hands and feet, consistent with a diagnosis of SRPS type III. Chorionic villus sampling was performed, and targeted next-generation sequencing (NGS) was applied to analyze a panel of 25 genes including CEP120, DYNC2H1, DYNC2LI1, EVC, EVC2, FGFR2, FGFR3, HOXD10, IFT122, IFT140, IFT172, IFT52, IFT80, KIAA0586, NEK1, PAPSS2, SLC26A2, SOX9, TCTEX1D2, TCTN3, TTC21B, WDR19, WDR34, WDR35 and WDR60. The NGS analysis identified novel mutations in the DYNC2H1 gene. The fetus was compound heterozygous for a missense mutation c.8077G > T (p.Asp2693Tyr) of paternal origin in DYNC2H1 and a frameshift mutation c.11741_11742delTT (p.Phe3914X) of maternal origin in DYNC2H1. The fetus had a karyotype of 46,XY, and postnatally manifested characteristic SRPS type III phenotype. CONCLUSION Targeted NGS is useful in genetic diagnosis of fetal skeletal dysplasia and SRPS, and the information acquired is helpful in genetic counseling.
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Affiliation(s)
- Chih-Ping Chen
- Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei, Taiwan; Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan; School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan; Institute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan; Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
| | - Tsang-Ming Ko
- Genephile Bioscience Laboratory, Ko's Obstetrics and Gynecology, Taipei, Taiwan
| | | | - Schu-Rern Chern
- Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan
| | - Shin-Wen Chen
- Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei, Taiwan
| | - Shih-Ting Lai
- Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei, Taiwan
| | - Tzu-Yun Chuang
- Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei, Taiwan
| | - Wayseen Wang
- Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan; Department of Bioengineering, Tatung University, Taipei, Taiwan
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Meirelles GV, Perez AM, de Souza EE, Basei FL, Papa PF, Melo Hanchuk TD, Cardoso VB, Kobarg J. “Stop Ne(c)king around”: How interactomics contributes to functionally characterize Nek family kinases. World J Biol Chem 2014; 5:141-160. [PMID: 24921005 PMCID: PMC4050109 DOI: 10.4331/wjbc.v5.i2.141] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2013] [Revised: 01/07/2014] [Accepted: 02/18/2014] [Indexed: 02/05/2023] Open
Abstract
Aside from Polo and Aurora, a third but less studied kinase family involved in mitosis regulation is the never in mitosis-gene A (NIMA)-related kinases (Neks). The founding member of this family is the sole member NIMA of Aspergillus nidulans, which is crucial for the initiation of mitosis in that organism. All 11 human Neks have been functionally assigned to one of the three core functions established for this family in mammals: (1) centrioles/mitosis; (2) primary ciliary function/ciliopathies; and (3) DNA damage response (DDR). Recent findings, especially on Nek 1 and 8, showed however, that several Neks participate in parallel in at least two of these contexts: primary ciliary function and DDR. In the core section of this in-depth review, we report the current detailed functional knowledge on each of the 11 Neks. In the discussion, we return to the cross-connections among Neks and point out how our and other groups’ functional and interactomics studies revealed that most Neks interact with protein partners associated with two if not all three of the functional contexts. We then raise the hypothesis that Neks may be the connecting regulatory elements that allow the cell to fine tune and synchronize the cellular events associated with these three core functions. The new and exciting findings on the Nek family open new perspectives and should allow the Neks to finally claim the attention they deserve in the field of kinases and cell cycle biology.
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Eleftheriades M, Iavazzo C, Manolakos E, Hassiakos D, Botsis D, Petersen M, Konstantinidou A. Recurrent short rib polydactyly syndrome. J OBSTET GYNAECOL 2012; 33:14-6. [DOI: 10.3109/01443615.2012.698334] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Chen CP, Chang TY, Chen CY, Wang TY, Tsai FJ, Wu PC, Chern SR, Wang W. Short rib-polydactyly syndrome type II (Majewski): prenatal diagnosis, perinatal imaging findings and molecular analysis of the NEK1 gene. Taiwan J Obstet Gynecol 2012; 51:100-5. [PMID: 22482978 DOI: 10.1016/j.tjog.2012.01.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/2011] [Indexed: 11/26/2022] Open
Abstract
OBJECTIVE To demonstrate perinatal imaging findings and to investigate the mutation in the NEK1 gene in a fetus with type II short rib-polydactyly syndrome (SRPS) (Majewski). CASE REPORT A 34-year-old woman with a past history of fetal SRPS was referred to the hospital at 16 weeks of gestation because of sonographic diagnosis of short limbs in the fetus. Fetal ultrasound revealed short ribs, short limbs, absence of tibiae, polydactyly, syndactyly and choroid plexus cysts. At 21 weeks of gestation, polycystic kidneys were found. The pregnancy was terminated, and a fetus was delivered with facial dysmorphism, a median cleft lip, a narrow chest, micromelia, aplasia of tibiae, hypoplastic nails, syndactyly and postaxial polydactyly. The karyotype was 46,XX. Molecular analysis of fetal tissues showed a paternal-origin heterozygous splice site mutation in intron 7 (c.465-1 G>A) in the NEK1 gene, but no mutations in the genes of WDR35, DYNC2H1, IFT80, EVC and EVC2. The NEK1 mutation causes an alteration of the splice acceptor site of intron 7 (IVS7-1 G>A). No second mutation was identified. CONCLUSION Tibial aplasia, choroid plexus cysts and polycystic kidneys can be prominent prenatal ultrasound findings of type II SRPS. The present case provides evidence for a correlation of NEK1 mutation with type II SRPS.
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Affiliation(s)
- Chih-Ping Chen
- Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan.
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Chen CP, Su YN, Hsu CY, Chern SR, Tsai FJ, Wu PC, Chen PT, Wang W. Ellis-van Creveld syndrome: prenatal diagnosis, molecular analysis and genetic counseling. Taiwan J Obstet Gynecol 2011; 49:481-6. [PMID: 21199751 DOI: 10.1016/s1028-4559(10)60101-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/2010] [Indexed: 12/26/2022] Open
Abstract
OBJECTIVE To present the perinatal findings and molecular genetic analysis of two siblings with Ellis-van Creveld (EvC) syndrome. MATERIALS, METHODS AND RESULTS A 33-year-old woman, gravida 3, para 1, was referred for genetic counseling at 18 gestational weeks because of recurrent fetal skeletal dysplasia. Two years previously, she had delivered a 1,316-g dead male baby at 28 gestational weeks with a karyotype of 46,XY, postaxial polydactyly of the hands, thoracic narrowness, endocardial cushion defects, transposition of the great arteries, shortening of the long bones, malposition of the toes, and hypoplastic nails. During this pregnancy, prenatal ultrasound at 18 gestational weeks revealed shortening of the long bones (equivalent to 15 weeks), postaxial polydactyly of both hands, thoracic narrowness, and endocardial cushion defects. The pregnancy was subsequently terminated, and a 236-g female fetus was delivered with a karyotype of 46,XX, postaxial polydactyly of the hands, thoracic dysplasia, endocardial cushion defects, shortening of the long bones, and malposition of the toes and hypoplastic nails. The phenotype of each of the two siblings was consistent with EVC syndrome. Molecular analysis of the EVC and EVC2 genes revealed heterozygous mutations in the EVC2 gene. A heterozygous deletion mutation of a 26-bp deletion of c.871-2_894del26 encompassing the junction between intron 7 and exon 8 of the EVC2 gene was found in the mother and two siblings, and a heterozygous nonsense mutation of c.1195C >T, p.R399X in exon 10 of the EVC2 gene was found in the father and two siblings. CONCLUSION Prenatal sonographic identification of endocardial cushion defects in association with shortening of the long bones should alert clinicians to the possibility of EvC syndrome and prompt a careful search of hexadactyly of the hands. Molecular analysis of the EVC and EVC2 genes is helpful in genetic counseling in cases with prenatally detected postaxial polydactyly, thoracic narrowness, short limbs and endocardial cushion defects.
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Affiliation(s)
- Chih-Ping Chen
- Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taichung, Taiwan.
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Abstract
Skeletal anomalies occur with a frequency of around 1:500 and can present a diagnostic challenge when detected prenatally. Increasingly more sophisticated imaging such as MRI or CT may elucidate features more easily interpreted by postnatal radiologists. The aetiology of these anomalies is varied and includes aneuploidy, genetic syndromes, skeletal dysplasias, teratogens, disruption and maternal disease, making a multidisciplinary approach to the diagnosis essential. The estimated prevalence of skeletal dysplasias varies from 2–3/10,000 to 4–7/10,000 and diagnosis may require biochemical, cytogenetic, molecular genetic or haematological investigation. Clinical genetic input is often required as the family history or parental examination may yield valuable clues to the diagnosis. This review will briefly describe the normal embryology and sonographic appearances of fetal limb development and go on to suggest a systematic approach to the diagnosis of fetal skeletal dysplasias.
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Current awareness in prenatal diagnosis. Prenat Diagn 2003; 23:522-8. [PMID: 12858868 DOI: 10.1002/pd.530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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