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.

Download Full-text

Intrafamilial Variability of the R694C Variant in BICD2 Presenting with Lethal Severe Arthrogryposis

Journal of Neonatology ◽

10.1177/09732179211068815 ◽

2022 ◽

pp. 097321792110688

Author(s):

Francisco Ribeiro-Mourão ◽

Ana Vilan ◽

Sara Passos-Silva ◽

Fernando Silveira ◽

Miguel Leão ◽

...

Keyword(s):

De Novo ◽

Bone Fractures ◽

Muscular Atrophy ◽

Hip Dislocation ◽

Arthrogryposis Multiplex Congenita ◽

Pathogenic Variants ◽

Genetic Abnormalities ◽

Heterozygous Variant ◽

Fetal Movements ◽

Intrafamilial Variability

Arthrogryposis multiplex congenita (AMC) is a heterogeneous condition comprising congenital multiple joint contractures, and it is secondary to decreased fetal mobility following environmental/genetic abnormalities. BICD2 pathogenic variants have been associated with autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED2). We report the case of a newborn with decreased fetal movements and ventriculomegaly diagnosed in utero, born with severe AMC, multiple bone fractures, congenital hip dislocation, and respiratory insufficiency that led to neonatal death. His mother had AMC diagnosis without established etiology. Her phenotype characterization was key to guide the genetic investigation. A BICD 2 heterozygous variant (NM_001003800.1; c.2080C > T; p. [Arg694Cys]) was detected both in the mother and the newborn. This variant had previously been reported in 3 cases, all having de novo severe SMALED-type 2B (MIM#618291) phenotype. This is the first report of this variant (p. [Arg694Cys]) presenting with an inherited, severe, and lethal phenotype associated to intrafamilial variability, suggesting a more complex phenotype-genotype correlation than previously stated.

Download Full-text

Identification of a mutational hostspot in the type II collagen gene (COL2A1): A common point mutation in two unrelated individuals with kniest dysplasia

Matrix Biology ◽

10.1016/0945-053x(94)90112-0 ◽

1994 ◽

Vol 14 (5) ◽

pp. 390 ◽

Cited By ~ 1

Author(s):

D.J. Wilkin ◽

R. Bogaert ◽

W.R. Wilcox ◽

D.L. Rimoin ◽

D.R. Eyre ◽

...

Keyword(s):

Point Mutation ◽

Type Ii Collagen ◽

Common Point ◽

Collagen Gene ◽

Type Ii ◽

Kniest Dysplasia

Download Full-text

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

Egyptian Journal of Radiology and Nuclear Medicine ◽

10.1186/s43055-021-00479-0 ◽

2021 ◽

Vol 52 (1) ◽

Author(s):

Saurabh Maheshwari ◽

Dilip Ingole ◽

Samar Chatterjee ◽

Uddandam Rajesh ◽

Varun Anand

Keyword(s):

Case Report ◽

Autosomal Dominant ◽

Antenatal Diagnosis ◽

Type Ii Collagen ◽

Type I ◽

Type Ii ◽

Rare Entity ◽

Case Presentation ◽

Structural Mutations ◽

Achondrogenesis Type

Abstract 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.

Download Full-text

Substitution of aspartic acid for glycine at position 310 in type II collagen produces achondrogenesis II, and substitution of serine at position 805 produces hypochondrogenesis: analysis of genotype-phenotype relationships

Biochemical Journal ◽

10.1042/bj3070823 ◽

1995 ◽

Vol 307 (3) ◽

pp. 823-830 ◽

Cited By ~ 17

Author(s):

J Bonaventure ◽

L Cohen-Solal ◽

P Ritvaniemi ◽

L Van Maldergem ◽

N Kadhom ◽

...

Keyword(s):

Type I Collagen ◽

Denaturing Gradient Gel Electrophoresis ◽

Type Ii Collagen ◽

Terminal Region ◽

Collagen Molecule ◽

Type I ◽

Type Ii ◽

Single Base ◽

Glycine Substitution ◽

Achondrogenesis Type

Two different mutations were found in two unrelated probands with lethal chondrodysplasias, one with achondrogenesis type II and the other with the less severe phenotype of hypochondrogenesis. The mutations in the COL2A1 gene were identified by denaturing gradient gel electrophoresis analysis of genomic DNA followed by dideoxynucleotide sequencing and restriction site analysis. The proband with achondrogenesis type II had a heterozygous single-base mutation that substituted aspartate for glycine at position 310 of the alpha 1(II) chain of type II procollagen. The proband with hypochondrogenesis had a heterozygous single-base mutation that substituted serine for glycine at position 805. Type II collagen extracted from cartilage from the probands demonstrated the presence of type I collagen and a delayed electrophoretic mobility, indicating post-translational overmodifications. Analysis of CNBr peptides showed that, in proband 1, the entire peptides were overmodified. Examination of chondrocytes cultured in agarose or alginate indicated that there was a delayed secretion of type II procollagen. In addition, type II collagen synthesized by cartilage fragments from the probands demonstrated a decreased thermal stability. The melting temperature of the type II collagen containing the aspartate-for-glycine substitution was reduced by 4 degrees C, and that of the collagen containing the serine-for-glycine substitution was reduced by 2 degrees C. Electron microscopy of the extracellular matrix from the chondrocyte cultures showed a decreased density of matrix and the presence of unusually short and thin fibrils. Our results indicate that glycine substitutions in the N-terminal region of the type II collagen molecule can produce more severe phenotypes than mutations in the C-terminal region. The aspartate-for-glycine substitution at position 310, which was associated with defective secretion and a probable increased degradation of collagen, is the most destabilizing mutation yet reported in type II procollagen.

Download Full-text

Identification of messenger RNA for human type II collagen

FEBS Letters ◽

10.1016/0014-5793(84)81165-5 ◽

1984 ◽

Vol 174 (2) ◽

pp. 238-242 ◽

Cited By ~ 3

Author(s):

E. Vuorio ◽

K. Elima ◽

J. Pulkkinen ◽

A.-M. Viitanen

Keyword(s):

Messenger Rna ◽

Type Ii Collagen ◽

Type Ii ◽

Human Type

Download Full-text

‘Isolated’ germline mosaicism in the phenotypically normal father of a girl with X-linked hypophosphatemic rickets

Acta Endocrinologica ◽

10.1530/eje-19-0472 ◽

2020 ◽

Vol 182 (1) ◽

pp. K1-K6 ◽

Cited By ~ 1

Author(s):

Yunting Lin ◽

Yanna Cai ◽

Jianan Xu ◽

Chunhua Zeng ◽

Huiying Sheng ◽

...

Keyword(s):

Sanger Sequencing ◽

De Novo ◽

Hypophosphatemic Rickets ◽

Dominant Inheritance ◽

Germline Mosaicism ◽

Pathogenic Variants ◽

First Case ◽

Heterozygous Variant ◽

The Family ◽

Normal Father

Objective X-linked hypophosphatemic rickets (XLHR) is the most common form of inherited rickets caused by pathogenic variants of PHEX gene with an X-linked dominant inheritance pattern. Precise molecular diagnosis of pathogenic variant will benefit the genetic counseling and prenatal diagnosis for the family with XLHR. Here, we presented an ‘isolated’ germline mosaicism in the phenotypically normal father of a girl with XLHR. Methods and results For the initial molecular screen of PHEX gene, DNA samples of the proband and her parents were extracted from their peripheral blood samples respectively. Sanger sequencing found a ‘de novo’ novel heterozygous variant, c.1666C>T(p.Q556X), at the PHEX gene in the proband, but not in her phenotypically healthy parents. Due to an occasional abnormality of his serum phosphate previously, further examinations for the father were taken to exclude the possibility of paternal mosaicism. Eight samples from different tissues were analyzed for PHEX gene by Sanger sequencing. Surprisingly, one ‘isolated’ germline mosaicism was detected only in his sperm with an estimated frequency of 26.67%. The mosaic allele was identical to the c.1666C>T(p.Q556X) variant in the proband. Conclusions This is the first case of ‘isolated’ germline mosaicism with pathogenic PHEX variant. Our study provides accurate diagnosis and valuable counseling for this family. This report also alerts clinicians and geneticists to exclude the possibility of the isolated germline mosaicism and prevent intrafamilial recurrences of inherited diseases.

Download Full-text