A novel compound heterozygous variant of the COL11A1 gene in a patient with fibrochondrogenesis type I: the first case in Korea

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Ann Pediatr Endocrinol Metab. 2024;29(2):135-137

Publication date (electronic) : 2024 April 30

doi : https://doi.org/10.6065/apem.2346150.075

Jaesung Jeon¹, Minji Kim¹, Sukdong Yoo¹, Yoomi Kim², Chong Kun Cheon^,1,3

¹Department of Pediatrics, Pusan National University Children’s Hospital, Pusan National University School of Medicine, Yangsan, Korea

²Department of Pediatrics, Chungnam National University College of Medicine, Daejeon, Korea

³Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea

Address for correspondence: Chong Kun Cheon Division of Pediatric Endocrinology, Department of Pediatrics, Pusan National University Children’s Hospital, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan 50612, Korea Email: chongkun@pusan.ac.kr

Received 2023 July 17; Revised 2023 September 3; Accepted 2023 December 12.

Highlights

· Fibrochondrogenesis (FBCG1) is a severe, autosomal recessive, short-limbed skeletal dysplasia caused by a variant in the COL11A1 gene. This is the first Korean report of FBCG1 which have a compound heterozygous variant of the COL11A1 gene and may provide insight into the phenotypic spectrum of FBCG1.

To the editor,

Fibrochondrogenesis type 1 (FBCG1, OMIM #228520) is a rare lethal autosomal recessive form of short-limbed skeletal dysplasia [1]. FBCG1 is caused by a mutation in the COL11A1 gene [1]. About 22 cases have been reported worldwide [2,3]. The disease is clinically characterized by short stature, skeletal anomalies, significant shortening of all limb segments, facial dysmorphism, myopia, cataracts, and sensorineural hearing loss [1,4,5]. Radiographically, the long bones are severely short and typically dumbbell-shaped with metaphyseal widening. Flat vertebral bodies and platyspondyly, a distinctive pear-shaped appearance, are observed on lateral view [1,4,5]. The disease was named on the basis of the abnormal morphology of the growth plate, in which the chondrocytes have a fibroblastic appearance and there are regions of fibrous cartilage extracellular matrix [1]. Clinically, patients with FBCG1 exhibit a wide clinical spectrum depending on their genotype.

Here, we report the first case of FBCG1 diagnosed by whole exome sequencing in Korea. A detailed interpretation of the identification of a novel variant in a single case of FBCG1 is included.

The patient was a boy 5 years and 11 month of age who was referred to the outpatient clinic due to short stature and webbed neck. He was delivered vaginally at 37+2 weeks of gestation at a birth weight of 2.66 kg. His father's height was 177 cm and his mother's height was 156 cm. He had a healthy sister and there was nothing noteworthy in the family pedigree.

At the time of the outpatient visit, the patient's height, body weight, and head circumference were 105.0 cm (-2.09 standard deviation score [SDS]), 17 kg (-1.85 SDS), 50.5 cm (-0.79 SDS), respectively. He had a dysmorphic facial appearance (Fig. 1), a narrow thorax, mild micromelia, and clinodactyly of both fifth digits. His bilateral wrist joints were flexed inward. Radiographically, the patient's spine was relatively straight, and the ribs exhibited broad metaphyseal cupping at the distal ends. The lumbar vertebral bodies demonstrated marked platyspondyly. He had achieved normal development milestones and was of normal intelligence.

Fig. 1.

Appearance of the patient at the initial visit. He had a dysmorphic appearance including hypertelorism, right ptosis, midface hypoplasia, long philtrum, low-set and rotated ear, anteverted nares, webbed neck, micrognathia, and triangular facial shape. His bilateral wrist joints were flexed inward.

At the first visit to our outpatient clinic, we performed a gene panel related to Noonan syndrome, with negative results. For further diagnosis, we performed whole exome sequencing (WES). Genomic DNA was extracted from buccal swab samples. All exons of all human genes (~22,000) were captured using Agilent's SureSelect kit (version C2, December 2018) and sequenced using the NovaSeq platform (Illumina, San Diego, CA, USA).

WES revealed bi-allelic variants in the COL11A1 gene. Sequence analysis of COL11A1 gene (NM_080629.2) revealed compound heterozygous variants in c.3478C>G (p.Pro1160Ala) on exon 45 and c.2771C>T (p.Pro924Leu) on exon 35 (Fig. 2), the former of which is a novel variant. The c.3478C>G variant was predicted to damage protein structure/function (REVEL score: 0.649≥0.6) and is absent from both gnomAD v2.1.1and v3 datasets. Initially, we classified this novel variant as a variant of uncertain significance, but later changed our classification to likely pathogenic after segregation analysis (trans). The compound heterozygous variants were derived from both the mother (p.Pro924Leu) and father (p.Pro1160Ala).

Fig. 2.

Whole exome sequencing found 2 heterozygous variants in the COL11A1 gene (NM_080629.3). Sequence analysis of the COL11A1 gene revealed compound heterozygous variants, c.3478C>G (p.Pro1160Ala) on exon 45 and c.2771C>T (p.Pro924Leu) on exon 35. Alignment of the predicted amino acid sequence of COL11A1 genes among different species, which is shown in the dotted red box. Sequences were aligned with blastp (https://blast.ncbi.nlm.nih.gov/).

After genetic diagnosis, the patient underwent ophthalmologic and audiometric assessments, which re vealed no complications. At the age of 12 years, his height was 145.5 cm (-1.00 SDS) and body weight was 36.9 kg (-1.12 SDS). His bone age was two years advanced relative to chronological age. He showed pubertal development corresponding to Tanner stage III. The patient's predicted adult height was expected to be 157 cm (-3.08 SDS).

The COL11A1 gene encodes the α1 chain of type XI collagen, is located at chromosome 1p21.1, and consists of 67 exons [1,6]. A novel variant for FBCG1, p.Pro1160Ala of the COL11A1 protein, is characterized by the base substitution of C to G at the nucleotide position 3478. This change is conserved across multiple species (Fig. 2). The p.Pro1160 residue is located on the cell surface proteins containing the conserved peptide motif (LPXTG)-anchored collagen-like adhesin Scl2/SclB domain.

Although there is no specific treatment for FBCG1, identification of variants in FBCG1 facilitates diagnostic testing for families and early detection of ophthalmic and hearing problems for parents, siblings, and other family members. Lukas et al. reported that treatment of three cases with COL11A1 mutations with growth hormone was effective, increasing growth velocity to 9.1 cm/year and height to SDS +1.5 during the first year of growth hormone treatment [7].

This is the first Korean report of FBCG1 with compound heterozygous mutations of the COL11A1 gene, and may provide insight into the phenotypic spectrum of FBCG1. If skeletal abnormalities are suspected in patients with short stature, immediate skeletal dysplasia-related next-generation sequencing is recommended.

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