Expanding the spectrum of short rib thoracic dysplasia case with a novel nonsynonymous and a synonymous variant in DYNC2H1

Expanding the spectrum of short rib thoracic dysplasia case with a novel nonsynonymous and a synonymous variant in DYNC2H1Bilgesu Ak1: (bilgesuak22@gmail.com), Mete Akısü2(mete.akisu@ege.edu.tr), Asude Durmaz1(asudealpman@gmail.com), Mehmet Yalaz2(mehmet.yalaz@ege.edu.tr), Demet Terek2(demet.terek@ege.edu.tr), Ayca Aykut1(ayca.aykut@ege.edu.tr)Bilgesu Ak ORCID ID: 0000-0002-0422-68701 Department of Medical Genetics, Ege University Hospital, Izmir, Turkey2 Department of Neonatalogy, Ege University Hospital, Izmir, TurkeyEthics Approval:The study was approved by the biomedical ethics committee at Ege University Hospital.Consent Statement:Written informed consent was obtained from the patient’s parents, because patient is under 16, to publish this report in accordance with the journal’s patient consent policy.Data Sharing Statement:All data generated or analyzed during this study are included in this published article.Funding:No funding of any kind or funding source was provided during the implementation and execution of this study.Competing interests:The authors declare that they have no competing interests.Acknowledgements:The authors would like to thank the patient for participating in this study.Abstract:Short rib thoracic dysplasia (SRTD), with or without polydactyly, also known as Verma-Naumoff/Saldino-Noonan syndrome, is a type of skeletal ciliopathy. Initially, the IFT80 gene was identified as the causative gene; however, half of the cases are caused by a homozygous or compound heterozygous mutation in the DYNC2H1 gene. Additionally, a digenic mutation involving DYNC2H1 and NEK genes can be responsible for the syndrome. Abnormalities in the skeletal system are essential, and visceral pathologies and metaphyseal findings help distinguish between different forms of SRTDs.In this case report, we present a male patient born in 2014 with phenotypic findings, including bitemporal narrowing, flattened nose, low-set and large uvula, constricted thorax, shortened upper and lower limbs, and clinodactyly in the second toes. There was no consanguinity between the parents, but there was a history of a deceased ex-sister with pulmonary hypoplasia and similar phenotypic findings. Whole exome sequencing (WES) analysis revealed a compound heterozygous mutation in the DYNC2H1 gene, consisting of a novel missense mutation c.6439G>T (p.Asp2147Tyr) and a synonymous mutation c.6477G>A (p.Gln2159=) in trans position. This report emphasizes the importance of considering synonymous variants and compound heterozygosity in patients with suspected diseases like short rib thoracic dysplasia, known for its genetic heterogeneity.Keywords: Short rib thoracic dysplasia; next-generation sequencing; clinical genomics; variant interpretation.Corresponding Author:Prof. Asude DurmazEge University Hospital Medical Genetics, 35100 Bornova, Izmir, Turkeyasudealpman@gmail.comIntroduction:Massively parallel sequencing has facilitated the identification of genetic causes underlying various diseases, particularly skeletal pathologies. As a result, the discovery of new genes and pathways associated with clinical and skeletal disorders has become possible. The Nosology Committee of the International Skeletal Dysplasia Society revised and updated the Nosology and Classification of Genetic Skeletal Disorders in 2019, which includes 461 diseases classified into 42 groups based on clinical, radiographic, and molecular phenotypic differences. Short rib thoracic dysplasia (SRTD) with or without polydactyly type 3 belongs to class 9, which includes ciliopathies with major skeletal involvement.Short rib thoracic dysplasia, also known as Verma-Naumoff/Saldino-Noonan syndrome, is an autosomal recessive or digenic recessive syndrome mainly caused by homozygous or compound heterozygous mutations in the dynein heavy chain, isotype 1B (DYNC2H1) gene, which is crucial for primary cilium function. Phenotypic findings include a constricted thoracic cage, short ribs, shortened tubular bones, and a ’trident’ appearance of the acetabular roof. Polydactyly can also be observed, and there is phenotypic overlap with other forms of SRTDs. The distinction between different forms of SRTDs is primarily based on concomitant visceral pathologies and metaphyseal findings, which may involve various major systems like the central nervous, cardiovascular, gastrointestinal, and genital systems. Due to its genetic heterogeneity, identifying biallelic pathogenic variants in presumed autosomal recessive cases can be challenging. Synonymous variants are often overlooked in bioinformatic analysis due to their high frequency and lack of impact on the amino acid sequence. However, investigating the pathogenicity of synonymous variants can improve the diagnosis in these cases inherited in an autosomal recessive or digenic recessive manner. Half of the cases were initially believed to be caused by mutations in the DYNC2H1 gene, but the gene’s large size (90 exons) and lack of mutational hotspots made genetic testing time-consuming and expensive. Consequently, clinical diagnosis was primarily relied upon. With the advancement of technology, whole exome sequencing (WES) has become the first-line method for identifying mutations in suspected cases. WES is a sensitive, specific, and cost-effective technique for mutation screening and gene discovery in SRTDs, providing a definitive diagnosis that allows for accurate patient counseling and preimplantation genetic diagnosis.Material and Methods:A 23-year-old woman (G2P1) in her 37th week of gestation, presenting with polyhydramnios, was admitted to the Ege University Hospital Women and Child’s Health department. A male baby weighing 2900 grams was born via C-section, and immediately after delivery, he experienced respiratory distress with an APGAR score of 3/7. Physical examination revealed tachypnea and intercostal retractions, along with phenotypic findings such as a narrow chest, short upper and lower limbs, bitemporal narrowing, flattened nasal root, low and large uvula, and clinodactyly in the second toes. Chest radiography showed a constricted thorax, short horizontally oriented ribs, short upper and lower limbs, and elevated clavicles. A skeletal survey revealed a narrow and elongated thorax, hypoplastic lungs, trident acetabulum, and short and thick bones in the arms and legs (Figure 1). Contrast-enhanced thoracic CT confirmed skeletal dysplasia and bilateral atelectatic areas in the lung parenchyma.