RhCE-D (2)-CE hybrid allele causing puzzle in serology and sequencing: a case report

The Rh locus, one of the important blood group systems in transfusion medicine, is controlled by three highly homologous genes: RHAG, RHD and RHCE. RHD and RHCE genes both contain 10 exons with opposite orientation, with genetic homology of higher than 92%. Based on this arrangement and configuration, a hybridization variant easily occurs, which causes variant or weak antigen expression. A 46-year-old woman of group A was admitted to hospital with bloody stool. Her RhD phenotype was confusing (agglutination < 1+) as detected by gel card. The unexpected antibody was identified to be anti-D. Only exon 2 of RHD was detected by sequence-specific primer polymerase chain reaction (SSP-PCR) with hybrid heterozygosis of c.150T>C, c.178A>C, c.201G>A, and c.307T>C by sequencing. The genotype of RHCE was confirmed to be Ccee by SSP-PCR and the serologic phenotype was Ccee too. However, the sequencing of RhCE was confirmed to be ccee with c.178CC, c.203AA, c.307CC on exon 2. Further analysis found that the difference between them depended on the replacement of exon 2 from RhD. The genotype of this patient was found to be RhCE-D(2)-CE/RhCE, leading to a conf using RhD phenotype.     

Wolfram syndrome: new mutations, different phenotype

Background

Wolfram Syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness identified by the acronym “DIDMOAD”. The WS gene, WFS1, encodes a transmembrane protein called Wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic β-cells and neurons. WS is a rare disease, with an estimated prevalence of 1/550.000 children, with a carrier frequency of 1/354.The aim of our study was to determine the genotype of WS patients in order to establish a genotype/phenotype correlation.

Methodology/Principal Findings

We clinically evaluated 9 young patients from 9 unrelated families (6 males, 3 females). Basic criteria for WS clinical diagnosis were coexistence of insulin-treated diabetes mellitus and optic atrophy occurring before 15 years of age. Genetic analysis for WFS1 was performed by direct sequencing.Molecular sequencing revealed 5 heterozygous compound and 3 homozygous mutations. All of them were located in exon 8, except one in exon 4. In one proband only an heterozygous mutation (A684V) was found. Two new variants c.2663 C>A and c.1381 A>C were detected.

Conclusions/Significance

Our study increases the spectrum of WFS1 mutations with two novel variants. The male patient carrying the compound mutation [c.1060_1062delTTC]+[c.2663 C>A] showed the most severe phenotype: diabetes mellitus, optic atrophy (visual acuity 5/10), deafness with deep auditory bilaterally 8000 Hz, diabetes insipidus associated to reduced volume of posterior pituitary and pons. He died in bed at the age of 13 years. The other patient carrying the compound mutation [c.409_424dup16]+[c.1381 A>C] showed a less severe phenotype (DM, OA).     

Long non-coding RNA POLR2E gene polymorphisms increased the risk of prostate cancer in a sample of the Iranian population

The current study aimed to examine the impact of POLR2E rs1046040 and rs3787016 polymorphisms on prostate cancer (PCa) risk in a sample of southeast Iranian population. The present case-control study was performed on 178 patients with PCa and 180 benign prostatic hyperplasia (BPH). Genotyping of the variants was done by mismatch PCR-RFLP. The findings showed that the rs3787016 C?>?T variant significantly increased the risk of PCa in codominant (OR?=?1.84, 95% CI?=?1.12-3.03, P?=?0.018, CT vs CC), dominant (OR?=?1.88, 95% CI?=?1.63-3.05, P?=?0.011, CT?+?TT vas CC) and allele (OR?=?1.77, 95% CI?=?1.52-2.72, P?=?0.010, T vs C) inheritance model. Regarding rs1046040 C?>?T polymorphism, the findings revealed that the CT genotype significantly increased the risk of PCa compared to the CC genotype (OR?=?1.60, 95% CI?=?1.03-2.49, P?=?0.043). Furthermore, rs3787016 CT/rs1046040?CC as well as rs3787016 CT/rs1046040 CT increased the risk of PCa compared to the CC/CC genotype (p?=?0.029 and p?=?0.014, respectively). Haplotype analysis proposed that rs3787016 T/rs1046040 C significantly increased the risk of PCa compared to C/C (p?=?0.037). No significant association was observed between POLR2E variants and clinicopathological characteristics of PCa patients. In conclusion, the findings propose that POLR2E variants may be a risk factor for susceptibility to PCa in a sample of Iranian population.     

<Emphasis Type="Italic">CBS</Emphasis> mutations and <Emphasis Type="Italic">MTFHR</Emphasis> SNPs causative of hyperhomocysteinemia in Pakistani children

Three index patients with hyperhomocysteinemia and ocular anomalies were screened for cystathionine beta synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) polymorphisms. Genotyping of hyperhomocysteinemia associated MTHFR polymorphisms C677T (rs1801133) and A1298C (rs1801131) was done by PCR-restriction fragment length polymorphism. Sanger sequencing was performed for CBS exonic sequences along with consensus splice sites. In the case of MTHFR polymorphisms, all the patients were heterozygous CT for the single nucleotide polymorphism (SNP) C677T and were therefore carriers of the risk allele (T), while the patients were homozygous CC for the risk genotype of the SNP A1298C. CBS sequencing resulted in the identification of two novel mutations, a missense change (c.467T>C; p.Leu156Pro) in exon 7 and an in-frame deletion (c.808_810del; p.Glu270del) in exon 10. In addition, a recurrent missense mutation (c.770C>T; p.Thr257Met) in exon 10 of the gene was also identified. The mutations were present homozygously in the patients and were inherited from the carrier parents. This is the first report from Pakistan where novel as well as recurrent CBS mutations causing hyperhomocysteinemia and lens dislocation in three patients from different families are being reported with the predicted effect of the risk allele of the MTHFR SNP in causing hyperhomocysteinemia.     

Four New Mutations and Two Polymorphic Variants of the Low-Density Lipoprotein Receptor Gene in Familial Hypercholesterolemia Patients from St. Petersburg

In a collection of DNA samples from 100 unrelated patients with clinical features of familial hypercholesterolemia (FH), a search for mutations of exons 4 and 10 of the low-density lipoprotein (LDL) receptor gene was performed using heteroduplex and single-strand conformational polymorphism (SSCP) analyses followed by sequencing of amplified DNA fragments. Four new mutations of the LDL receptor gene were identified: C146R (c.499 T > C), A130P (c.451 G > C), G128G (c.477 T > C), and C188Y (c.626 G > A). Mutation A130P was assigned to the same chromosome with allele variant 447C. Two polymorphic sites in exon 10 of the LDL receptor gene (1413G/A and 1545C/T) were found in the Russian population for the first time. Based on the data obtained, familial hypercholesterolemia was confirmed in seven patients.     

Four new mutations and polymorphic variants of the low density lipoprotein receptor in patients with familial hypercholesterolemia in Saint Petersburg

In a collection of DNA samples from 100 unrelated patients with clinical features of familial hypercholesterolemia (FH), a search for mutations of exons 4 and 10 of the low-density lipoprotein (LDL) receptor gene was performed using heteroduplex and single-strand conformational polymorphism (SSCP) analyses followed by sequencing of amplified DNA fragments. Four new mutations of the LDL receptor gene were identified: C146R (c.499 T > C), A130P (c.451 G > C), G128G (c.477 T > C), and C188Y (c.626 G > A). Mutation A130P was assigned to the same chromosome with allele variant 447C. Two polymorphic sites in exon 10 of the LDL receptor gene (1413G/A and 1545C/T) were found in the Russian population for the first time. Based on the data obtained, familial hypercholesterolemia was confirmed in seven patients.     

The Rhesus site

The Rhesus (Rh) blood group system is the most important blood group system in hemolytic disease of the fetus and newborn (HDFN). In clinical transfusions, the D antigen in the Rh blood group system comes third, behind antigens A and B which from ABO blood group system. Over the past decade, molecular technologies have been used to investigate the RHD allele in different ethnic groups. This review first introduces the basic structure of RhD protein and coding genes, then focuses on D-negative, weak D, partial D, DEL, RhD_null variants reported in the Chinese population. To date, more than 460 RHD variants have been reported around the world, but less than 70 RHD variants have been reported in the Chinese population. Further research is needed to identify more RHD polymorphism and establish criteria for blood detection and transfusion guidelines for RHD variants. Only in this way can we better guarantee the safety of blood transfusion and prevent the occurrence of HDFN. With the accumulation of research and clinical data, we should be clearer which RHD variants are to be regarded as RhD negative and which need to be regarded as RhD positive.     

A novel single nucleotide polymorphism in the coding region of goat growth hormone receptor gene and its association with lactose content and somatic cell count in milk

A novel single nucleotide polymorphism—a C/T transition (RFPL-MspI) was found upon sequencing of a 439 bp DNA fragment, comprising whole exon 4 and parts of adjacent introns of the goat growth hormone receptor gene. This mutation was located at 8th nucleotide of exon 4 (position 94 according to GenBank Acc. No. AY739707). The nucleotide substitution has no effect on the amino acid sequence of the GHR protein. Within the cohort of 227 Polish dairy goats three genotypes were found: CC (frequency 0.96), CT (0.036), and TT (0.004). The frequency of C and T alleles was 0.978 and 0.022, respectively. It was shown that CC genotype goats had significantly higher lactose content and lower somatic cell count than those with the CT genotype. No association was found with the other milk production traits studied.     

Association of SGK1 gene polymorphisms with type 2 diabetes

The serum and glucocorticoid inducible kinase SGK1 is genomically upregulated by glucocorticoids and in turn stimulates a variety of carriers and channels including the renal epithelial Na(+) channel ENaC and the intestinal Na(+) glucose transporter SGLT1. Twin studies disclosed an association of a specific SGK1 haplotype with moderately enhanced blood pressure in individuals who are carrying simultaneously a homozygous genotype for a variant in intron 6 [I6CC] and a homozygous or heterozygous genotype for the C allele of a polymorphism in exon 8 [E8CC/CT] of the SGK1 gene. A subsequent study confirmed the impact of this risk haplotype on blood pressure. SGK1 knockout mice are resistant to the insulin and high salt induced increase of blood pressure, glucocorticoid induced increase of electrogenic glucose transport, and glucocorticoid induced suppression of insulin release. The present study explored whether the I6CC/E8CC/CT haplotype impacts on the prevalence of type 2 diabetes. The prevalence of the I6CC genotype was 3.1% in a healthy German, 2.4 % in a healthy Romanian and 11.6 % in a healthy African population from Ghana (p=0.0006 versus prevalence in Caucasians). Comparison of genotype frequencies between type 2 diabetic patients and the respective control groups revealed significant differences for the intron 6 T>C variant. Carriers of at least one T allele were protected against type 2 diabetes (Romanians: p=0.023; OR 0.29; 95% CI 0.09-0.89; Germans: p=0.01; OR 0.37; 95% CI 0.17-0.81). The SGK1 risk haplotype (I6CC/E8CC/CT) was significantly (p=0.032; OR 4.31, 95% CI 1.19-15.58) more frequent in diabetic patients (7.2 %) than in healthy volunteers from Romania (1.8%). The observations support the view that SGK-1 may participate in the pathogenesis of metabolic syndrome.     

Clinical case of acral hemorrhagic Darier's disease is not caused by mutations in exon 15 of the ATP2A2 gene

Darier's disease (Dyskeratosis follicularis, DD) is a genetic disorder characterized by pathogenetic changes of keratinization with variant forms of cutaneous phenotype. Recently, it has been showed that Darier's disease cause mutations in the ATP2A2 gene, at 12q24.1. The gene encodes sarco-endoplasmic reticulum calcium ATPase type 2 (SERCA2). Mutations in exon 15 are reported to be the most consistent mutations associated with the acral hemorrhagic type of Darier's disease. By direct sequencing we investigated exon 15 of the ATP2A2 gene in a Croation family in which one member had a hemorrhagic Darier's disease, but did not record any mutation in the family we investigated. Our results show that mutations in exon 15 of the ATP2A2 gene are not a necessary prerequisite for acral hemorrhagic type of Darier's disease. Our finding support the variability of clinical manifestations of Darier's disease and lack of genotype/phenotype consistency.     

A New Polymorphism Biomarker rs629367 Associated with Increased Risk and Poor Survival of Gastric Cancer in Chinese by Up-Regulated miRNA-let-7a Expression

Background

Variant in pri-miRNA could affect miRNA expression and mature process or splicing efficiency, thus altering the hereditary susceptibility and prognosis of cancer. We aimed to assess miRNA-let-7 single nucleotide polymorphisms (SNP) associated with the risk and prognosis of gastric cancer (GC) as predicting biomarkers, and furthermore, its possible mechanisms.

Methods

A two-stage case-control study was designed to screen four miRNA SNPs (pri-let-7a-2 rs629367 and rs1143770, pri-let-7a-1 rs10739971, pri-let-7f-2 rs17276588) in 107 GC patients, 107 atrophic gastritis (AG), and matched 124 controls using PCR-RFLP. Two promising SNPs were validated in another independent 1949 samples (including 579 gastric cancer patients, 649 atrophic gastritis and 721 controls) using Sequenom MassARRAY platform and sequencing.

Results

We found that pri-let-7a-2 rs629367 CC variant genotype was associated with increased risks of gastric cancer and atrophic gastritis by 1.83-fold and 1.86-fold, respectively. For gastric cancer prognosis, patients with rs629367 CC genotype had significantly poorer survival than patients with AA genotype (log-rank P = 0.004). We further investigated the let-7a expression levels in serum and found that let-7a expression elevated gradually for rs629367 AA, CA, CC genotype in the atrophic gastritis group (P = 0.043). Furthermore, we confirmed these findings in vitro study by overexpressing let-7a carrying pri-let-7a-2 wild-type A or polymorphic-type C allele (P<0.001).

Conclusions

pri-let-7a-2 rs629367 CC genotype could increase the risks of gastric cancer as well as atrophic gastritis and was also associated with poor survival of gastric cancer, which possibly by affecting the mature let-7a expression, and could serve as a predicting biomarker for high-risk and poor prognosis of gastric cancer.     

Whole-exome sequencing reveals a recurrent mutation in the cathepsin C gene that causes Papillon–Lefevre syndrome in a Saudi family

Papillon–Lefevre syndrome (PALS) is a rare, autosomal recessive disorder characterized by periodontitis and hyperkeratosis over the palms and soles. Mutations in the cathepsin C gene (CTSC) have been recognized as the cause of PALS since the late 1990s. More than 75 mutations in CTSC have been identified, and phenotypic variability between different mutations has been described. Next generation sequencing is widely used for efficient molecular diagnostics in various clinical practices. Here we investigated a large consanguineous Saudi family with four affected and four unaffected individuals. All of the affected individuals suffered from hyperkeratosis over the palms and soles and had anomalies of both primary and secondary dentition. For molecular diagnostics, we combined whole-exome sequencing and genome-wide homozygosity mapping procedures, and identified a recurrent homozygous missense mutation (c.899G>A; p.Gly300Asp) in exon 7 of CTSC. Validation of all eight family members by Sanger sequencing confirmed co-segregation of the pathogenic variant (c.899G>A) with the disease phenotype. This is the first report of whole-exome sequencing performed for molecular diagnosis of PALS in Saudi Arabia. Our findings provide further insights into the genotype–phenotype correlation of CTSC pathogenicity in PALS.     

中国广东汉族人群核苷酸修复基因hMTH1 遗传多态性研究

为研究中国南方汉族人群核苷酸修复基因hMTH1遗传多态性,应用聚合酶链反应-单链构象多态性技术检测172名健康人外周血白细胞hMTH1基因启动子及全部5个外显子多态性,并进行DNA测序。结果发现hMTH1基因启动子及外显子1序列保守,未见突变;外显子2第73位碱基存在T→C杂合型突变,基因型TT和TC频率分别为93.02%、6.98%,等位基因T和C频率分别为96.51%、3.49％;外显子3第45位遗传密码存在T→C杂合型突变,基因型TT和TC频率分别为95.35%、4.65%,等位基因T和C频率分别为97.67%、2.33%,该多态性为首次发现;外显子4第83位遗传密码存在G→A杂合型突变,基因型GG和GA频率分别为89.53%、10.47%,等位基因G和A频率分别为94.77%、5.23％;外显子5第119位氨基酸遗传密码存在C→T杂合型突变,基因型CC和CT频率分别为95.93%、4.07%,等位基因C和T频率分别为97.97%、2.03％。Abstract: In order to study the genetic polymorphisms of nucleotide repair gene hMTH1 in southern Chinese Han population, the polymorphisms of the gene’s promoter and its five exons among peripheral blood lymphocytes of 172 Chinese Han people were analyzed with polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and DNA sequencing. The sequences of the promoter and exon 1 of hMTH1 gene were conserved. A T to C polymorphism was detected at the 73th base in exon2. The genotype frequencies of TT and TC were 93.02% and 6.98%, respectively. The allelic frequencies of T and C were 96.51% and 3.49％, respectively. A T to C polymorphism was detected at codon 45 in exon3, which was first reported. The genotype frequencies of TT and TC were 95.35% and 4.65%, respectively. The allelic frequencies of T and C were 97.67% and 2.33%, respectively. A G to A polymorphism was detected at codon 83 in exon4. The genotype frequencies of GG and GA were 89.53% and 10.47%, respectively. The allelic frequencies of G and A were 94.77% and 5.23％, respectively. A C to T polymorphism was detected at codon 119 in exon5. The genotype frequencies of CC and CT were 95.93% and 4.07%, respectively. The allelic frequencies of C and T were 97.97% and 2.03％, respectively.     

A novel homozygous mutation in <Emphasis Type="Italic">SZT2</Emphasis> gene in Saudi family with developmental delay,macrocephaly and epilepsy

Epileptic encephalopathies are genetically heterogeneous disorders which leads to epilepsy and cause neurological disorders. Seizure threshold 2 (SZT2) gene located on chromosome 1p34.2 encodes protein mainly expressed predominantly in the parietal and frontal cortex and dorsal root ganglia in the brain. Previous studies in mice showed that mutation in this gene can confers low seizure threshold, enhance epileptogenesis and in human may leads to facial dysmorphism, intellectual disability, seizure and macrocephaly. Objective of this study was to find out novel gene or novel mutation related to the gene phenotype. We have identified a large consanguineous Saudi family segregating developmental delay, intellectual disability, epilepsy, high forehead and macrocephaly. Exome sequencing was performed in affected siblings of the family to study the novel mutation. Whole exome sequencing data analysis, confirmed by subsequent Sanger sequencing validation study. Our results showed a novel homozygous mutation (c.9368G>A) in a substitution of a conserved glycine residue into a glutamic acid in the exon 67 of SZT2 gene. The mutation was ruled out in 100 unrelated healthy controls. The missense variant has not yet been reported as pathogenic in literature or variant databases. In conclusion, the here detected homozygous SZT2 variant might be the causative mutation that further explain epilepsy and developmental delay in this Saudi family.     

不同海拔高原鼠兔个性特征与SERT基因多态性关联

个性特征是指动物个体间稳定、可遗传的行为差异,与相关基因多态性有关,反映了动物对环境的适应模式,探究个性相关基因变异,将有助于更好地理解动物对环境的适应与进化机制。本文以高原鼠兔 (Ochotona curzoniae) 为对象,研究了5个不同海拔地区高原鼠兔的个性 (探究性、勇敢性和温顺性) 差异特征,并检测了个性相关基因5-羟色胺转运体 (SERT) 的单核苷酸多态性 (SNP) 和mRNA表达。结果发现,高海拔地区高原鼠兔的探究性和勇敢性显著高于低海拔地区,而高海拔地区高原鼠兔SERT基因mRNA表达量显著低于低海拔地区,提示不同海拔高原鼠兔个性特征差异可能与SERT基因mRNA表达有所关联。进一步检测不同海拔地区高原鼠兔SERT基因多态性及其分布差异情况,发现该基因存在6个SNP (其中5个位于外显子3,1个位于外显子5 );不同海拔地区鼠兔基因分布差异分析显示外显子5的c.A1063C 同义突变与海拔之间存在显著相关,高海拔地区该位点CC基因型分布频率显著高于低海拔地区;c.A1063C的基因型虽然与探究性、勇敢性无显著相关,但与温顺性显著相关。综上所述,随着海拔升高,高原鼠兔探究性和勇敢性增加,这有利于动物获取更多的食物资源,进而增加其生存机会。与此同时,SERT基因多态性显示与不同海拔地区的生存环境相适应的特征,且与温顺性有关,暗示不同海拔高原鼠兔个性差异可能与SERT基因SNP的差异有关。本研究从基因表达与突变的角度尝试阐述高原鼠兔适应不同海拔环境的行为差异,显示了不同海拔地区高原鼠兔行为生存策略潜在的分子机制。     

Association between polymorphisms in the SLC27A1 gene and milk production traits in Chinese Holstein cattle

We assessed SLC27A1, a candidate gene for milk production traits in Chinese Holstein cattle. DNA was extracted from the blood of 48 top Chinese Holstein Cattle selected according to phenotypic character and mixed into DNA pool for SNP detection. We tested blood samples of these cattle for SNPs in exon 3 and the 3'-flanking region of the SLC27A1 gene by using polymerase chain reaction-single-stranded conformation polymorphism (PCR-SSCP) and DNA sequencing. We found 2 polymorphic sites: 112T>C, a synonymous mutation, in exon 3 (SNP(1)), and 64G>A in the 3'-UTR (SNP(2)). We also determined the genotypes of 330 Chinese Holstein cattle by using PCR-restriction fragment length polymorphism (RFLP). We found 3 genotypes each at SNP(1) (TT, TC, and CC) and SNP(2) (GG, GA, and AA). The association among the different genotypes at these 2 sites and milk production traits was analyzed using a least-squares procedure. The results showed that cows with genotype CC had higher milk yields than those with genotype TC (0.01 < p < 0.05). No significant difference was detected among the 3 SNP(2) genotypes in terms of milk production traits. Our results provide evidence that the C allele have potential effects on milk yield trait.     

秦川牛脂联素基因SNPs检测及其与胴体、肉质性状的相关性

利用PCR-SSCP结合测序技术对405头24月龄秦川牛脂联素基因SNPs位点进行检测, 运用SPSS统计程序中的GLM模型将检测到的SNPs位点与部分胴体及肉质性状的相关性进行了分析。结果检测到AA、AB、BB、CC、CD 5种基因型, 其中AB、BB型个体在脂联素基因第2外显子 64 bp处发现G→C突变, CD型个体第3外显子50 bp处发现C→T的突变, G→C导致谷氨酸(GGA)转化为谷氨酰胺(GCA), C→T导致丝氨酸(TCA)转化为亮氨酸(TTA)。方差分析结果表明: AA型个体的宰前活重、胴体重、眼肌面积显著高于BB型(P<0.05), 而在胴体腿臀围方面, AA型个体极显著高于AB型、BB型个体(P<0.01)。CD型个体的宰前活重、胴体腿臀围、皮下脂肪厚、背膘厚、嫩度都显著优于CC型个体(P<0.05)。脂联素基因该位点可能是影响秦川牛胴体及肉质性状的主效QTL或与之紧密连锁, 可作为秦川牛高档牛肉生产的候选分子标记。     

Molecular genetic characterization of ovine CSN1S2 variants C and D reveal further important variability within CSN1S2

Within this study, the recently identified ovine CSN1S2 variants C and D were characterized at the molecular genetic level. Sequencing of the cDNA and of parts of the DNA identified several sequence differences within CSN1S2*C and D in comparison to CSN1S2*A and B. CSN1S2*C is characterized by two non-synonymous single nucleotide polymorphisms (SNPs) within exon 7 (c.178A>G, c.187G>T) leading to the amino acid substitutions p.Val45Ile and p.Ala48Ser. CSN1S2*D is caused by the SNP c.183G>C, leading to an amino acid replacement at position 46 (p.Arg46Ser). A very common c.527G>A-SNP within exon 15, resulting in the amino acid substitution p.Arg161His and producing the new variant CSN1S2*G, not detectable by isoelectric focusing and previously misidentified as CSN1S2*A, was also identified. On the basis of the identified sequence differences, a new nomenclature is proposed and a possible phylogenetic pathway shown for ovine CSN1S2 variants.     

A Novel missense mutation of COL2A1 gene in a large family with stickler syndrome type I

Stickler syndrome type I (STL1, MIM 108300) is characterized by ocular, auditory, skeletal and orofacial manifestations. Nonsyndromic ocular STL1 (MIM 609508) characterized by predominantly ocular features is a subgroup of STL1, and it is inherited in an autosomal dominant manner. In this study, a novel variant c.T100>C (p.Cys34Arg) in COL2A1 related to a large nonsyndromic ocular STL1 family was identified through Exome sequencing (ES). Bioinformatics analysis indicated that the variant site was highly conserved and the pathogenic mechanism of this variant may involve in affected structure of chordin‐like cysteine‐rich (CR) repeats of ColIIA. Minigene assay indicated that this variant did not change alternative splicing of exon2 of COL2A1. Moreover, the nonsyndromic ocular STL1 family with 16 affected members showed phenotype variability and certain male gender trend. None of the family members had hearing loss. Our findings would expand the knowledge of the COL2A1 mutation spectrum, and phenotype variability associated with nonsyndromic ocular STL1. Search for genetic modifiers and related molecular pathways leading to the phenotype variation warrants further studies.