Skip to main content
NCBI home page
Molecular Genetics & Genomic Medicine logoLink to Molecular Genetics & Genomic Medicine
. 2023 Jul 23;11(10):e2242. doi: 10.1002/mgg3.2242

Prenatal whole exome sequencing identified two rare compound heterozygous variants in EVC2 causing Ellis‐van Creveld syndrome

Jianlong Zhuang 1,✉, Shufen Liu 2, Junyu Wang 1, Yu'e Chen 3, Hegan Zhang 4, Yuying Jiang 1, Gaoxiong Wang 5,✉, Chunnuan Chen 2,✉
PMCID: PMC10568384  PMID: 37485807

Abstract

Background

Pathogenic mutations in EVC or EVC2 gene can lead to Ellis‐van Creveld (EvC) syndrome, which is a rare autosomal recessive skeletal dysplasia disorder. This study aimed to determine pathogenic gene variations associated with EvC syndrome in fetuses showing ultrasound anomalies.

Methods

A 32‐year‐old pregnant woman from Quanzhou, China was investigated. In her pregnancy examination, the fetus exhibited multiple fetal malformations, including a narrow thorax, short limbs, postaxial polydactyly, cardiac malformations, and separation of double renal pelvis. Karyotype, chromosomal microarray analysis and whole exome sequencing were performed for prenatal genetic etiology analysis.

Results

Chromosome abnormalities and copy number variants were not observed in the fetus using karyotype and chromosomal microarray analysis. Using whole exome sequencing, two compound heterozygous variants NM_147127.5:c.[2484G>A(p.Trp828Ter)];[871‐2_894del] in EVC2 gene were identified in the fetus as pathogenic variants inherited from parents.

Conclusions

The study is the first to identify two rare compound variants in EVC2 gene in a Chinese family using whole exome sequencing. The application of whole‐exome sequencing would be helpful in fetal etiological diagnosis with ultrasound anomalies.

Keywords: chromosomal microarray analysis, Ellis‐van Creveld syndrome, EVC2, prenatal diagnosis, whole exome sequencing

We first identified two rare compound variants in EVC2 gene in a Chinese family using whole exome sequencing. In addition, we further enhanced that application of whole exome sequencing would be helpful in fetal etiological diagnosis with ultrasound anomalies.

graphic file with name MGG3-11-e2242-g002.jpg

1. BACKGROUND

Ellis‐van Creveld (EvC) syndrome [Online Mendelian Inheritance in Man (OMIM) #225500] is an autosomal recessive skeletal ciliopathies, which characterized by short ribs, short limbs, postaxial polydactyly, ectodermal dysplasia (such as dysplastic nails and teeth, sparse hair and an absent gingival sulcus), heart defects (Baujat & Le Merrer, 2007). The incidence in general population is low, and an increased frequency has been reported in the Amish community in Lancaster Country, Pennsylvania, US (McKusick, 2000; McKusick et al., 1964). To date, it is know that EvC syndrome is caused by pathogenic mutations in the EVC gene (OMIM #604831) or EVC2 gene (OMIM #607261) and presents variable phenotypes. In addition, the molecular understanding of the genetic mutations in EVC and EVC2 genes should be further understood, as these gene variations could also be associated with an autosomal dominant disorder of Weyers acrodental dysostosis, which typically exhibit postaxial polydactyly with anomalies of the lower jaw, dentition and oral vestibule (Weyers, 1952).

The Jeune syndrome (208500) and McKusick‐Kaufman (MKKS; #236700) syndromes are clinically similar to EvC syndrome. Among them, there is phenotypic overlap in the various forms of short‐rib thoracic dysplasia, while differ by visceral malformation and metaphyseal appearance (Huber & Cormier‐Daire, 2012). The main visceral abnormality in Jeune syndrome or asphyxiating thoracic dystrophy is renal and hepatic, whereas it is cardiac in EvC syndrome (Oberklaid et al., 1977). Additionally, prominent features in EvC syndrome are osteochondrodysplasia and ectodermal anomalies, whereas hydrometrocolpos in MKKS that cause by homozygous or compound heterozygous variants in the MKKS gene (OMIM #604896) (Schaefer et al., 2011). Moreover, the cranioectodermal dysplasia (OMIM #218330) is an autosomal recessive disorder characterized by sagittal craniosynostosis and facial, ectodermal, and skeletal anomalies (Gilissen et al., 2010), which also shares many features in common with EvC syndrome.

Currently, reports of EvC syndrome are limited to the Chinese population. This study reports a clinical case of fetal anomalies showing short limbs, postaxial polydactyly, cardiac malformations, and separation of double renal pelvis. Two rare compound heterozygous variants in EVC2 gene were identified, suggesting a close association with EvC syndrome.

2. METHODS

2.1. Ethical compliance

Ethical approval was obtained from the Institutional Ethics Committee of Quanzhou Women's and Children's Hospital at the commencement of this study (2020No.31).

2.2. Karyotype analysis

Chromosome karyotype analysis was performed using the SinochromeChromprepII automatic chromosome harvesting system (Shanghai Lechen Biotechnology Co., Ltd, China) according to standard laboratory protocols. Cytogenomic nomenclature of the karyotypes were conducted according to International System for Human Cytogenomic Nomenclature (ISCN 2020).

2.3. Molecular analysis

Aborted tissue of the fetus and parental peripheral blood were collected for genomics DNA extraction using QIAamp DNA Blood Kit (QIAGEN, Germany), which were further used for chromosomal microarray analysis and WES analysis. The prepared genomics DNA was first used for chromosomal microarray analysis using the AffymetrixCytoScan™ 750K chip, following the Affymetrix CytoScan assay user guide (http://www.thermofisher.com) (Zhuang et al., 2023).

Subsequently, the genomics DNA were subject to WES analysis. The genomics DNA were sheared to an approximate mean fragment length of 150–200 bp using the Covaris LE220 (Covaris, Woburn, MA, USA). The sequencing libraries were quantified using an Illumina DNA Standards and Primer Premix Kit (Kapa Biosystems, Boston, MA, USA). The whole exome sequencing was performed on the Illumina HiSeq 2500 platform (Illumina, San Diego, CA, USA) (Zhuang et al., 2023).

3. RESULTS

3.1. Clinical description

A family from Quanzhou, China was enrolled in this study. The pregnant woman was 32‐year‐old, gravida 2, para 1, and the couple denied consanguineous marriage and any inherited disease. Their first child was a girl born at a gestational age of 35+1 weeks in 2019, with 2.38 kg in weight (below 3 percentile) and height of 48 cm (17 percentile). By the time of this study, the first child was three years old, 95 cm (45 percentile) in height and 14.6 kg (60 percentile) in weight, showing normal development. In the second pregnancy, nuchal translucency (NT) was detected as normal (1.5 mm, 40 percentile). In the second trimester, screening for Down syndrome showed low‐risk screening results. However, TIFFA Scan (Targeted imaging for fetal anomalies) examination at the gestational age of 22+2 weeks revealed that the fetus had a narrow thorax, short limbs, postaxial polydactyly, cardiac malformations, and separation of double renal pelvis (Figure 1). Amniocentesis was performed at a gestational age of 23+5 weeks for further molecular analysis.

FIGURE 1.

FIGURE 1

Open in a new tab

The ultrasound anomalies detected in the fetus by prenatal ultrasound examination. (a) Prenatal ultrasound examination indicates a narrow thorax in the fetus. A single atrium and ventricular septal defect (b), significantly short femur (c) and short left upper limb (d) were also observed in the fetus on prenatal ultrasound examination. As shown in (e) and (f), postaxial polydactyly was present in left hand and foot of the fetus, respectively.

3.2. Molecular analysis

Chromosome abnormalities and copy number variants were not detected in the fetus using karyotype and chromosomal microarray analysis.

The DNA variants detected by whole exome sequencing (WES) were prioritized followed the pipeline as described by Chen et al. (2022). We manually transferred the clinical signs in to Human Phenotype Ontology (HPO) terms and a published phenotypic scoring algorithm Phrank based on HPO terms was employed to assist in prioritizing alterations. Then the variants were filtered with inheritance mode, allele frequency, silico prediction. All the candidate variants were reviewed for brief clinical correlation. The WES results revealed two compound heterozygous variants NM_147127.5:c.[2484G>A(p.Trp828Ter)];[871‐2_894del], in EVC2 gene, and Sanger sequencing confirmed that the two genetic variants were inherited from his father and mother, respectively (Figure 2). The c.2484G>A (p.Trp828Ter) variant presented no frequency in 1000 genomes database, but a low frequency in gnomAD Exomes, gnomAD Genomes, and frequency based on BRAVO database (0.00002, 0.0000132, 0.00000756, respectively). In addition, the c.2484G>A (p.Trp828Ter) variant was interpreted as pathogenic/likely pathogenic variant in ClinVar database. The other c.871‐2_894del variant showed no frequency in 1000 genomes database and gnomAD Genomes, but a low frequency in gnomAD Exomes and Bravo (0.00000398 and 0.0000113, respectively), and was also classified as pathogenic/likely pathogenic variant in ClinVar database. According to the American College of Medical Genetics and Genomics (ACMG) guidelines (Richards et al., 2015), these two variants were classified as pathogenic variants [Pathogenic Very Strong 1 (PVS1), Pathogenic Moderated (PM)‐2_supporting, PM‐3; PVS1, PM‐2_supporting, PM‐3, Pathogenic Supporting 1 (PP1)]. Further pedigree Sanger sequencing results demonstrated that the first child also carried c.871‐2_894del variant in EVC2 gene transmitted from her mother, and exhibit normal phenotype. In addition, none of pathogenic variants in other genes that could causing similar clinical features were observed.

FIGURE 2.

FIGURE 2

Open in a new tab

Identification of two variants in EVC2 gene in the enroll family. (a, b) Two rare compound heterozygous variants NM_147127.5:c.[2484G>A(p.W828*)];[871‐2_894del] in EVC2 gene in the fetus were confirmed by Sanger sequencing. (c, d) The c.2484G>A(p.W828*) heterozygous variant was observed in the father of the fetus without carrying the c.871‐2_894del variant. (e, f) The c.871‐2_894del heterozygous variant was observed in the fetus's mother, whereas the c.2484G>A (p.W828*) variant was absent.

After genetic counseling, the family chose to terminate the pregnancy. A male baby was delivered, the clinical features (Figure 3) were consistent with prenatal ultrasound examination results, whereas autopsy was not available.

FIGURE 3.

FIGURE 3

Open in a new tab

The clinical phenotypes of the fetus after delivery. (a, b) Postaxial polydactyly was observed in both hands and left foot after delivery. (c, d) In addition, a narrow thorax and short limbs were also observed in the fetus.

4. DISCUSSION

Despite the advanced performance of chromosome microarray analysis in prenatal diagnosis, most of the cases remain undiagnosed. Ng et al. (2010) first applied WES for sequence variant detection to clarify the correlations between phenotypes and genotypes in rare inherited diseases. In recent clinical practice, it has been suggested for used in prenatal diagnosis when ultrasonic structural abnormalities are observed (Lord et al., 2019; Petrovski et al., 2019). In the present study, a prenatal examination at a gestational age of 22 weeks detected ultrasound anomalies, and WES identified gene variants association with EvC syndrome.

EvC syndrome is a rare autosomal recessive skeletal dysplasia disorder characterized by short ribs, short limbs, postaxial polydactyly, and ectodermal dysplasia, heart defects and other congenital disorder, with a high incidence in the Amish community in Lancaster Country. The prevalence in the non‐Amish population is approximately 0.7 in 100,000 (McKusick, 2000). EvC syndrome can be diagnosed prenatally using ultrasound examination. Variable structural fetal defects, including narrow thorax, short and bowed long bones, rounded metaphyses, postaxial polydactyly, and cardiac defect, may suggest a diagnosis of EvC syndrome (Baujat & Le Merrer, 2007). In this case study, the patient with EvC syndrome presented a few of the mentioned clinical features, such as narrow thorax, short limbs, postaxial polydactyly, and cardiac malformations. NT thickening is usually associated with EvC syndrome (Venkat‐Raman et al., 2005). However, normal NT was observed in the present case. In addition, ectodermal dysplasia with thin sparse hair, hypodontic and abnormally formed teeth can also be present in patients with EvC syndrome, which can not be identified by ultrasonography. The variety of phenotypes could led to misdiagnosis and genetic examination could improve the accuracy of the prenatal diagnosis.

Pathogenic mutations in EVC gene or EVC2 gene have been reported to cause EvC syndrome. EVC and EVC2 are single‐pass type I transmembrane proteins that regulate signaling pathway during embryonic development. EVC2 is located on chromosome 4p16, with 22 coding exons spanning 150 kb of genomic DNA. It was also found that the transcription start sites of EVC and EVC2 were separated by only 1643 basepairs (Galdzicka et al., 2002; Ruiz‐Perez et al., 2003).

As shown in the Human Gene Mutation Database (HGMD) database, most EVC and EVC2 gene variants associated with EvC syndrome are nonsense mutations, splicing and frameshift mutations, and truncating protein. In our WES analysis, a stop‐gain variant c.2484G>A compound with a splicing variant c.871‐2_894del was first detected in a Chinese male fetus. The c.2484G>A variant was previously found to be heterozygous in a Japanese individual with bone dysplasia (Nagaoka et al., 2021). The c.871‐2_894del a rare splicing variant was first reported by Chen et al. (2010). Our study reported the second case carrying c.871‐2_894del variant as new evidence to support the role of the gene variant leading to EvC syndrome. The other variant of c.2484G>A was reported to be recurrent nonsense mutation associated with EvC syndrome showing distal limb shortening and polydactyly (Zhang et al., 2012). In EvC syndrome, there is a 25% recurrence risk of family reproduction. Understanding the genetic risks associated with EvC syndrome is an important task, which will help to achieve a more accurate prenatal diagnosis.

In conclusion, our study is the first to identify two rare compound variants of EVC2 gene in a Chinese population that associate with EvC syndrome. The detected variants expanded the recognition of pathogenic genetic variants for EvC syndrome. The result is a good example of prenatal diagnosis of fetal defects with postaxial polydactyly, thoracic narrowness, congenial heart defects, and short limbs.

AUTHOR CONTRIBUTIONS

Jianlong Zhuang wrote the article; Shufen Liu, Yuying Jiang, Yu'e Chen, Junyu Wang and Hegan Zhang recruited the participants, performed clinical consultation and analyzed the data; Chunnuan Chen, Gaoxiong Wang and Jianlong Zhuang revised and polished the paper. All authors approved the final article.

FUNDING INFORMATION

This research was Sponsored by Fujian Provincial Health Technology Project (2020QNB045); the Key Project on the Integration of Industry, Education and Research Collaborative Innovation of Fujian Province (2021YZ034011); the Key Project on Science and Technology Program of Fujian Health Commission (2021ZD01002) and Quanzhou City Science and Technology Program of China (2020C026R, 2023NS068).

CONFLICT OF INTEREST STATEMENT

The authors declared no conflict of interest.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Ethics Committee approval was obtained from the Institutional Ethics Committee of Quanzhou women's and children's hospital to the commencement of the study (2020No.31). All patients signed consent forms and agreed to the use of relevant data and information for scientific research.

CONSENT FOR PUBLICATION

We confirmed that the parents participated in this study have signed the consent to allow their own and their children's genetic data and relevant information to be published or externally released.

ACKNOWLEDGMENTS

We here express our appreciation to Fujian Provincial Health Commission and Quanzhou City Science and Technology Bureau for funding this work. We also express our appreciation to the patients who participate in this study.

Zhuang, J. , Liu, S. , Wang, J. , Chen, Y. , Zhang, H. , Jiang, Y. , Wang, G. , & Chen, C. (2023). Prenatal whole exome sequencing identified two rare compound heterozygous variants in EVC2 causing Ellis‐van Creveld syndrome. Molecular Genetics & Genomic Medicine, 11, e2242. 10.1002/mgg3.2242

Contributor Information

Jianlong Zhuang, Email: 415913261@qq.com.

Gaoxiong Wang, Email: wanggaoxiong2013@163.com.

Chunnuan Chen, Email: chenchunnuan1983@aliyun.com.

DATA AVAILABILITY STATEMENT

The datasets were used and analyzed during the current study available from the corresponding author on reasonable request.

REFERENCES

  1. Baujat, G. , & Le Merrer, M. (2007). Ellis‐van Creveld syndrome. Orphanet Journal of Rare Diseases, 2, 27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chen, C. P. , Su, Y. N. , Hsu, C. Y. , Chern, S. R. , Tsai, F. J. , Wu, P. C. , Chen, P. T. , & Wang, W. (2010). Ellis‐van Creveld syndrome: Prenatal diagnosis, molecular analysis and genetic counseling. Taiwanese Journal of Obstetrics & Gynecology, 49(4), 481–486. [DOI] [PubMed] [Google Scholar]
  3. Chen, X. , Jiang, Y. , Chen, R. , Qi, Q. , Zhang, X. , Zhao, S. , Liu, C. , Wang, W. , Li, Y. , Sun, G. , Song, J. , Huang, H. , Cheng, C. , Zhang, J. , Cheng, L. , & Liu, J. (2022). Clinical efficiency of simultaneous CNV‐seq and whole‐exome sequencing for testing fetal structural anomalies. Journal of Translational Medicine, 20(1), 10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Galdzicka, M. , Patnala, S. , Hirshman, M. G. , Cai, J. F. , Nitowsky, H. , Egeland, J. A. , & Ginns, E. I. (2002). A new gene, EVC2, is mutated in Ellis‐van Creveld syndrome. Molecular Genetics and Metabolism, 77(4), 291–295. [DOI] [PubMed] [Google Scholar]
  5. Gilissen, C. , Arts, H. H. , Hoischen, A. , Spruijt, L. , Mans, D. A. , Arts, P. , van Lier, B. , Steehouwer, M. , van Reeuwijk, J. , Kant, S. G. , Roepman, R. , Knoers, N. V. A. M. , Veltman, J. A. , & Brunner, H. G. (2010). Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome. American Journal of Human Genetics, 87(3), 418–423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Huber, C. , & Cormier‐Daire, V. (2012). Ciliary disorder of the skeleton. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 160C(3), 165–174. [DOI] [PubMed] [Google Scholar]
  7. Lord, J. , McMullan, D. J. , Eberhardt, R. Y. , Rinck, G. , Hamilton, S. J. , Quinlan‐Jones, E. , Prigmore, E. , Keelagher, R. , Best, S. K. , Carey, G. K. , Mellis, R. , Robart, S. , Berry, I. R. , Chandler, K. E. , Cilliers, D. , Cresswell, L. , Edwards, S. L. , Gardiner, C. , Henderson, A. , … Prenatal Assessment of Genomes and Exomes Consortium . (2019). Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): A cohort study. Lancet, 393(10173), 747–757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. McKusick, V. A. (2000). Ellis‐van Creveld syndrome and the Amish. Nature Genetics, 24(3), 203–204. [DOI] [PubMed] [Google Scholar]
  9. McKusick, V. A. , Egeland, J. A. , Eldridge, R. , & Krusen, D. E. (1964). Dwarfism in the Amish I. The Ellis‐Van Creveld Syndrome. Bulletin of the Johns Hopkins Hospital, 115, 306–336. [PubMed] [Google Scholar]
  10. Nagaoka, S. , Yamaguchi‐Kabata, Y. , Shiga, N. , Tachibana, M. , Yasuda, J. , Tadaka, S. , Tamiya, G. , Fuse, N. , Kinoshita, K. , Kure, S. , Murotsuki, J. , Yamamoto, M. , Yaegashi, N. , & Sugawara, J. (2021). Estimation of the carrier frequencies and proportions of potential patients by detecting causative gene variants associated with autosomal recessive bone dysplasia using a whole‐genome reference panel of Japanese individuals. Hum Genome Var., 8(1), 2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ng, S. B. , Buckingham, K. J. , Lee, C. , Bigham, A. W. , Tabor, H. K. , Dent, K. M. , Huff, C. D. , Shannon, P. T. , Jabs, E. W. , Nickerson, D. A. , Shendure, J. , & Bamshad, M. J. (2010). Exome sequencing identifies the cause of a mendelian disorder. Nature Genetics, 42(1), 30–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Oberklaid, F. , Danks, D. M. , Mayne, V. , & Campbell, P. (1977). Asphyxiating thoracic dysplasia. Clinical, radiological, and pathological information on 10 patients. Archives of Disease in Childhood, 52(10), 758–765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Petrovski, S. , Aggarwal, V. , Giordano, J. L. , Stosic, M. , Wou, K. , Bier, L. , Spiegel, E. , Brennan, K. , Stong, N. , Jobanputra, V. , Ren, Z. , Zhu, X. , Mebane, C. , Nahum, O. , Wang, Q. , Kamalakaran, S. , Malone, C. , Anyane‐Yeboa, K. , Miller, R. , … Wapner, R. J. (2019). Whole‐exome sequencing in the evaluation of fetal structural anomalies: A prospective cohort study. Lancet, 393(10173), 758–767. [DOI] [PubMed] [Google Scholar]
  14. Richards, S. , Aziz, N. , Bale, S. , Bick, D. , das, S. , Gastier‐Foster, J. , Grody, W. W. , Hegde, M. , Lyon, E. , Spector, E. , Voelkerding, K. , Rehm, H. L. , & ACMG Laboratory Quality Assurance Committee . (2015). 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. Genetics in Medicine, 17(5), 405–424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ruiz‐Perez, V. L. , Tompson, S. W. , Blair, H. J. , Espinoza‐Valdez, C. , Lapunzina, P. , Silva, E. O. , Hamel, B. , Gibbs, J. L. , Young, I. D. , Wright, M. J. , & Goodship, J. A. (2003). Mutations in two nonhomologous genes in a head‐to‐head configuration cause Ellis‐van Creveld syndrome. American Journal of Human Genetics, 72(3), 728–732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Schaefer, E. , Durand, M. , Stoetzel, C. , Doray, B. , Viville, B. , Hellé, S. , Danse, J. M. , Hamel, C. , Bitoun, P. , Goldenberg, A. , Finck, S. , Faivre, L. , Sigaudy, S. , Holder, M. , Vincent, M. C. , Marion, V. , Bonneau, D. , Verloes, A. , Nisand, I. , … Dollfus, H. (2011). Molecular diagnosis reveals genetic heterogeneity for the overlapping MKKS and BBS phenotypes. European Journal of Medical Genetics, 54(2), 157–160. [DOI] [PubMed] [Google Scholar]
  17. Venkat‐Raman, N. , Sebire, N. J. , Murphy, K. W. , Carvalho, J. S. , & Hall, C. M. (2005). Increased first‐trimester fetal nuchal translucency thickness in association with chondroectodermal dysplasia (Ellis‐van Creveld syndrome). Ultrasound in Obstetrics & Gynecology, 25(4), 412–414. [DOI] [PubMed] [Google Scholar]
  18. Weyers, H. (1952). Uber eine korrelierte Missbildung der Kiefer‐ und Extremitätenakren [A correlated abnormality of the mandible and extremities (dysostosis acrofacialis)]. Fortschritte Auf Dem Gebiete der Röntgenstrahlen, 77(5), 562–567. [PubMed] [Google Scholar]
  19. Zhang, Z. , Bao, K. , He, J. W. , Fu, W. Z. , Zhang, C. Q. , & Zhang, Z. L. (2012). Identification of one novel mutation in the EVC2 gene in a Chinese family with Ellis‐van Creveld syndrome. Gene, 511(2), 380–382. [DOI] [PubMed] [Google Scholar]
  20. Zhuang, J. , Luo, Q. , Xie, M. , Chen, Y. , Jiang, Y. , Zeng, S. , Wang, Y. , Xie, Y. , & Chen, C. (2023). Etiological identification of recurrent male fatality due to a novel NSDHL gene mutation using trio whole‐exome sequencing: A rare case report and literature review. Molecular Genetics & Genomic Medicine, 11(3), e2121. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets were used and analyzed during the current study available from the corresponding author on reasonable request.

Articles from Molecular Genetics & Genomic Medicine are provided here courtesy of Blackwell Publishing

RESOURCES