NH SRCC Children's Hospital, 1-1A, Keshavrao Khadye Marg, Haji Ali, Haji Ali Government Colony, Mahalakshmi, Mumbai, Maharashtra, 400034, India.
FRIGE's Institute of Human Genetics, FRIGE House, Jodhpur Gam Road, Satellite, Ahmedabad, 380015, India.
BMC Pediatr. 2021 Mar 6;21(1):113. doi: 10.1186/s12887-021-02582-7.
Bi-allelic mutations in FAM20C gene are known to cause a rare genetic disorder- Raine syndrome (RS). The FAM20C protein binds calcium and phosphorylates proteins involved in biomineralization of bones and teeth. RS is recognized as an osteosclerotic bone dysplasia. It is characterized by distinctive facial features, generalized osteosclerosis and respiratory insufficiency along with periosteal bone formation. RS is typically described as being an aggressive skeletal dysplasia with death in the neonatal period or early infancy. However, in the recent past an increasing number of individuals having an extended life span along with a highly heterogeneous phenotype has led to classifying RS into short and extended lifespan categories.
We report a case of RS with antenatal fractures, facial dysmorphism and osteosclerosis without significant respiratory manifestations. The child has a relatively extended lifespan, whereby she died at 17-months of age. Clinical exome sequencing revealed a previously known, homozygous, nonsense variant c.1680C > A (p.Cys560Ter) in exon 10 of FAM20C. Whilst the variant was initially classified as a variant of uncertain significance (VUS), through the latest release of gnomAD and GTEx data, this was subsequently re-classified as likely pathogenic. Furthermore, segregation analysis showed both parents to be carriers. In contrast, a previously reported case with the same variant had polyhydramnios, complex facial abnormalities and bright echogenic brain parenchyma with oval shaped skull and anterior flattening at 26 weeks of gestation.
The variant identified has been previously reported as a VUS. The present case provides further evidence towards the pathogenicity of the variant. A plausible genotype-phenotype correlation based on the location of the variant has been verified, wherein the position of a nonsense variant in the terminal exon of FAM20C gene, could have had a partial effect on the protein function, thereby resulting in a relatively milder phenotype and extended lifespan. Furthermore, the vast phenotypic variation on clinical comparison current case and a previously reported case, despite having the same genotype, could suggest an oligogenic effect and/ or environmental influence.
已知 FAM20C 基因的双等位基因突变会导致一种罕见的遗传疾病——Raine 综合征（RS）。FAM20C 蛋白结合钙并磷酸化参与骨骼和牙齿生物矿化的蛋白质。RS 被认为是一种骨质硬化性骨发育不良。其特征为独特的面部特征、全身性骨质硬化和呼吸功能不全，同时伴有骨膜骨形成。RS 通常被描述为一种侵袭性骨骼发育不良，新生儿期或婴儿早期死亡。然而，在最近，越来越多的具有延长寿命和高度异质表型的个体导致将 RS 分为短寿命和长寿命类别。
我们报告了一例具有产前骨折、面部畸形和骨质硬化但无明显呼吸表现的 RS 病例。该患儿具有相对延长的寿命，17 个月时死亡。临床外显子组测序显示 FAM20C 第 10 外显子中存在一个先前已知的纯合无义变异 c.1680C > A（p.Cys560Ter）。虽然该变异最初被归类为意义不明的变异（VUS），但通过最新版 gnomAD 和 GTEx 数据，该变异随后被重新归类为可能致病性。此外，分离分析显示父母均为携带者。相比之下，先前报道的一例具有相同变异的病例在 26 孕周时出现羊水过多、复杂的面部异常和明亮的脑实质回声增强，呈椭圆形颅骨和前扁平。
已鉴定的变异先前被报道为 VUS。本病例提供了进一步证据证明该变异的致病性。基于变异位置的合理基因型-表型相关性已得到验证，其中 FAM20C 基因末端外显子中的无义变异的位置可能对蛋白功能产生部分影响，从而导致相对较轻的表型和延长的寿命。此外，尽管具有相同的基因型，但与先前报道的病例相比，目前病例的临床表现存在巨大差异，这可能提示存在寡基因效应和/或环境影响。
