Balkan Journal of Medical Genetics

ACHONDROGENESIS TYPE 2 IN A NEWBORN WITH A NOVEL MUTATION ON THE COL2A1 GENE
Dogan P1,*, Varal IG1, Gorukmez O2, Akkurt MO3, Akdag A1
*Corresponding Author: Pelin Dogan, M.D., University of Health Sciences, Bursa Yuksek Ihtisas Teaching Hospital, Department of Pediatrics, Division of Neonatology, Yıldırım, Bursa, Turkey. Tel.: +90-505-316-4268. Fax: +90-224-294-4000. E-mail: pelin_akbas@yahoo.com
page: 89

CASE REPORT

A 25-year-old pregnant Syrian woman was referred to the perinatology clinic for further screening due to a suspected skeletal anomaly at 27 weeks’ gestation. The previous obstetric history was uneventful and the couple was non consanguineous. The first trimester screening was negative, while a detailed sonography scan revealed short long bones (<1st percentile for all long bones, including femur, tibia, fibula, humerus, radius and ulna) with a small thorax and polihydroamnios. The family was provided genetic counseling related to the high suspicion of lethal skeletal dysplasia. After detailed counseling, a cordocentesis was performed. All sonographic findings suggested skeletal dysplasia; a conventional chromosomal analysis confirmed a normal 46,XY karyotype, while an exome sequencing analysis revealed ACG2. After a 10-week follow-up period, a cesarean delivery was carried out at 39 weeks’ gestation due to a previous history of cesarean section. The patient had a 1 and 5 min. APGAR score of 4 and 5 at birth, respectively. The patient was intubated after delivery due to a lack of spontaneous respiration and was admitted to the Level III Neonatal Intensive Care Unit (NICU), Bursa, Turkey. The birth weight was 2780 gr (3-10 percentile), height was 38 cm (below 3 percentile), and head circumference was 37 cm (90-97 percentile). A physical examination revealed extremely short extremities, abdominal distention, a small chest, a prominent forehead and a flat nasal bridge (Figure 1). Ophthalmological examination of the patient was normal. The patient had severe respiratory distress, and follow-up was continued with high frequency oscillation ventilation (HFOV), as conventional mechanical ventilator settings failed to achieve the target saturation level. A peripheral vascular line could not be established due to extensive edema in the body, for which an umbilical catheter was inserted and total parenteral nutrition was initiated. A cranial and abdominal ultrasound revealed normal findings, while an X-ray examination revealed a short tubular bone structure, metaphyseal widening, short ribs, a small chest and a lack of ossification in the pelvis (Figure 2). A blood sample was obtained for genetic analysis with an antenatal pre diagnosis of ACG2. An echocardiography performed on postnatal day 4 revealed pulmonary hypertension and the patient was administered nitric oxide therapy for 2 days. Respiratory distress persisted in the follow-up period and the patient was followed with HFOV due to carbon dioxide retention with conventional ventilator settings. The patient died of respiratory insufficiency on postnatal day 25. Genetic Analysis. In the present study, clinical exome sequencing and Sanger sequencing were performed, and genomic DNA was extracted from peripheral venous blood using a QIAamp® DNA Mini Kit (Qiagen, Ankara, Turkey). The Clinical Exome Solution (Sophia Genetics SA, Saint-Sulpice, Switzerland) was used for exome enrichment, with all procedures carried out according to the manufacturer’s protocols. This capture-based target enrichment kit covers 4900 genes with known inherited diseases causing mutations. Paired-end sequencing was performed on a NextSeq 500 system (Illumina, San Diego, CA, USA) with a read length of 150 × 2, while the base calling and image analysis were conducted using Real-Time Analysis (integrated to the NextSeq 500 system; Illumina) software. The BCL (base calls) binary is converted into FASTQ utilizing the Illumina package bcl2fastq. All bioinformatic analyses were performed on a Sophia DDM™ platform (Sophia Genetics SA), which includes algorithms for alignment, calling single nucleotide polymorphisms (SNPs) and small insertions/deletions (Pepper™, Sophia Genetics SA patented algorithm) calling copy number variations (Muskat™, Sophia Genetics SA patented algorithm) and functional annotations (Moka™, Sophia Genetics SA patented algorithm). The raw reads were aligned to the human reference genome (GRCh37/ hg19). Variant filtering and interpretations were performed on the Sophia DDM™ platform (Sophia Genetics SA), and an Integrative Genomics Viewer (IGV) was used to visualize the BAM (binary alignment map) files [5]. In families with consanguineous marriages, homozygosity mapping is carried out with HomSI (www.igbam.bilgem. tubitak. gov.tr/softwares/ HomSI) [6]. Next generation sequencing (NGS) showed a heterozygous missense variation, c.2546G>A, p.Gly849Asp on the COL2A1 gene that was confirmed by Sanger sequencing (Figure 3). Genetic Results. This variant (c.2546G>A, p.Gly849Asp) on the COL2A1 gene has not been previously reported in the Human Gene Mutation Database (HGMD; http://www.hgmd.cf.ac.uk/ac/index.php) or in population studies (ExAC: Exome Aggregation Consortium and 1000 Genomes Project), while silico analysis programs (VarSome; DANN Score: 0.9969 and ACMG; Likely Pathogenic) have shown that this variation may be the cause of the disease.

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