A Novel Splicing Variant of COL2A1 in a Fetus with Achondrogenesis Type II: Interpretation of Pathogenicity of In-Frame Deletions

Achondrogenesis type II (ACG2) is a lethal skeletal dysplasia caused by dominant pathogenic variants in COL2A1. Most of the variants found in patients with ACG2 affect the glycine residue included in the Gly-X-Y tripeptide repeat that characterizes the type II collagen helix. In this study, we reported a case of a novel splicing variant of COL2A1 in a fetus with ACG2. An NGS analysis of fetal DNA revealed a heterozygous variant c.1267-2_1269del located in intron 20/exon 21. The variant occurred de novo since it was not detected in DNA from the blood samples of parents. We generated an appropriate minigene construct to study the effect of the variant detected. The minigene expression resulted in the synthesis of a COL2A1 messenger RNA lacking exon 21, which generated a predicted in-frame deleted protein. Usually, in-frame deletion variants of COL2A1 cause a phenotype such as Kniest dysplasia, which is milder than ACG2. Therefore, we propose that the size and position of an in-frame deletion in COL2A1 may be relevant in determining the phenotype of skeletal dysplasia.

A case report of achondrogenesis type II (Langer-Saldino achondrogenesis)

Background Achondrogenesis type II is a rare autosomal dominant skeletal dysplasia with a frequency of ~0.2 per 100,000 births. It is one of the lethal short-limbed dwarfisms associated with structural mutations in type II collagen and is also known as Langer-Saldino achondrogenesis. It is characterized by severe micromelia (shortening of entire limb), narrow chest, and prominent abdomen. It shares the striking feature of partial or complete vertebral body demineralization with achondrogenesis type I. Case presentation We present a case with antenatal diagnosis of this rare entity which was confirmed by post-termination radiographs of abortus. Conclusion The imaging plays a cardinal role in the diagnosis of this condition. This case represents only the 4th case of this rare entity from India.

Achondrogenesis type 2 in a newborn with a novel mutation on the COL2A1 gene

Achondrogenesis is a group of rare and fatal disorders occurring in approximately one in every 40,000-60,000 newborns. Achondrogenesis is classified in three groups, as Achondrogenesis type 1A (Houston-Harris type or AC-G1A), Achondrogenesis type 1B (Parenti-Fraccaro type or ACG1B) and Achondrogenesis type 2 (Langer-Saldino type or ACG2), depending on clinical and radiological findings. Achondrogenesis Type 2 is a lethal skeletal dysplasia that is typically characterized by short arms and legs, a small chest with short ribs, lung hypoplasia, a prominent forehead, a small chin, and an enlarged abdomen that may accompanied by polydramnios and hydrops. This study contributes to the literature by presenting a patient who was admitted to the Level ΙΙΙ Neonatal Intensive Care Unit (NICU), Bursa, Turkey), with extremely short extremities, a small chest, abdominal distention and respiratory distress, who was diagnosed with ACG2. On the COL2A1 gene, genetic analysis with next generation sequencing (NGS), was revealed to have a heterozygous missense variation, c.2546G>A, p.Gly849Asp mutation, which is a different genetic variant that has not been previously described in the literature.

Diagnosis of Prenatal-Onset Achondrogenesis Type II by a Multidisciplinary Assessment: A Retrospective Study of 2 Cases

Aim. Achondrogenesis type II is a rare, lethal osteochondrodysplasia with considerable phenotypic heterogeneity. We describe our experience in diagnosing prenatal-onset achondrogenesis type II by a multidisciplinary assessment. Methods. Two cases of fetal achondrogenesis type II were analyzed retrospectively using prenatal ultrasound evaluation, postnatal radiographic diagnosis, and molecular genetic testing of COL2A1. Results. A causative mutation in the COL2A1 gene was found in both patients. Combined with postnatal radiographic examination, the final diagnosis of achondrogenesis type II was made. Conclusion. Our findings emphasize the importance of a multidisciplinary assessment for the definitive diagnosis of achondrogenesis type II, which is paramount for proper genetic counseling.

Spondylo-Epi-Metaphyseal and Spondylo-Metaphyseal Dysplasias

This chapter further discusses bone dysplasias and explores achondrogenesis type 1A, odontochondrodysplasia, Schneckenbecken dysplasia, opsismodysplasia, spondylometaphyseal dysplasia (Sedaghatian type), spondyloenchondrodysplasia, SEMD (PAPSS2 type) and brachyolmia (autosomal recessive type), Dyggve-Melchior-Clausen dysplasia, spondylometaepiphyseal dysplasia (short limb-abnormal calcification type), spondylometaphyseal dysplasia with cone-rod dystrophy, dyssegmental dysplasia, Schwartz-Jampel syndrome, spondyloepiphyseal dysplasia tarda (X-linked), aggrecan-associated skeletal dysplasias, Wolcott-Rallison syndrome, Schimke immunoosseous dysplasia, progressive pseudorheumatoid chondrodysplasia, spondylometaphyseal dysplasia (corner fracture type), sponastrime dysplasia, CODAS syndrome, N-acetyl-neuraminic acid synthase (NANS) deficiency, and spondylo-epi-metaphyseal dysplasia with immune deficiency and developmental disability (EXTL3-deficient type). Each discussion includes major radiographic features, major clinical findings, genetics, major differential diagnoses, and a bibliography.