179 A novel misense mutation of col2a1 gene as a cause of short extremeties in two first cousins

Abstract

Introduction: Etiopathogenesis of fetal limb abnormalities involves genetic disorders, intrauterine factors, and maternal disease or exposure, while in many cases it remains unknown. Aim: We present two related cases (first cousins) of short limbed fetuses caused by a novel mutation of COL2A1 gene (NM_001844.5). Case 1 description: A 29.24-year-old pregnant woman with an uncomplicated pregnancy, presented for b-scan. Limbs were found to be well below the 3rd centile for gestational age. Initial fetal genetic work-up (targeted) was negative and the rest of the maternal follow-up was unremarkable. A healthy baby was delivered and the pediatric follow-up for an SGA child was appropriate. On second pregnancy a normal baby was born. Case 2 description: A 33.01-year-old pregnant woman with an uncomplicated pregnancy, presented for 3rd trimester Doppler scan. Limbs were found to be well below the 1rd centile for gestational age. Given that the two cases were related (first cousins) whole exome sequencing (WES) was performed on Case 2. WES revealed a novel heterozygous missense mutation c.1132G>A (p. Gly378Ser) of COL2A1 gene (NM_001844.5). Subsequently targeted genetic sequencing for the mutation was performed on Case 1 and the same novel mutation was found, making it potentially pathogenic. Targeted sequencing revealed the same mutation in the mother of Case 1 and the Father of Case 2 (siblings). Discussion: Heterozygous mutations of COL2A1 have been associated with broad clinical spectrum (collagenopathy type II), ranging from lethal to the fetus to mild appearing in adult life as early arthritis. More frequently they appear as skeletal dysplasia with ocular, hearing, and craniofacial findings. Conclusion: Ultrasonography has allowed increasingly accurate detection of skeletal abnormalities in utero. Efficient genetic assessment as part of an MDT approach can lead to a quick diagnosis and elucidation of novel genetic causes and appropriate pediatric follow-up of the child.