Novel Variants of CEP152 in a Case of Compound-Heterozygous Inheritance of Epilepsy
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Abstract Introduction CEP152 encodes protein Cep152, which associates with centrosome function. The lack of Cep152 can cause centrosome duplication to fail. CEP152 mutates, causing several diseases such as Seckel syndrome-5 and primary microencephaly-9. Methods In this study, we reported a patient diagnosed with epilepsy in Tianjin Children's Hospital. We performed clinical examination and laboratory test, and whole-exome sequencing was performed for the proband's and his parents' peripheral blood. The suspected compound-heterozygous variant in the CEP152 gene was verified by Sanger sequencing and quantitative real-time polymerase chain reaction technology. Results We discovered three variants—two of them from CEP152 and one from HPD. The result showed the variants in CEP152 only. The patient presented with seizures frequently. Sanger sequencing showed two novel variants in CEP152 are in exon26 (NM_014985.3 c.3968C > A p.Ser1323*) and in exon16 (NM_014985.3 c.2034_2036del p.Tyr678*). Conclusions We reported a novel compound-heterozygous variant in the CEP152 gene in this study. Most of the phenotypes are Seckel syndrome and primary microencephaly, and the novel variant may cause an atypical phenotype that is epilepsy.Keywords:
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A. The family pedigree. B. Whole exome sequencing of the proband-parent trio revealed c.611_612dupTG(p.M205*) variant of FITM2 gene as suspicious variant. C. Sanger sequencing confirmed that c.611_612dupTG(p.M205*) variant of FITM2 gene was homozygous in the proband, while the unaffected parents were heterozygous.
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Objective: To explore the genetic characteristics of a family with hereditary hemorrhagic telangiectasia (HHT) caused by endoglin (ENG) gene mutations. Methods: A total of 17 individuals from a 3-generation HHT family attending the First Affiliated Hospital of Dali University were selected as the research subjects. Clinical data and familial disease status of the HHT family proband were collected. Whole exome sequencing technology was used to screen for suspected pathogenic genes in the proband, and Sanger sequencing was used for family validation. Results: The proband and her mother had recurrent epistaxis and skin mucosal telangiectasia, and enhanced CT scans of the chest of the proband and her mother, daughter, and cousin indicated the presence of varying degrees of pulmonary arteriovenous malformations. The results of the full exon sequencing results showed that the proband carried the ENG gene c.579_599del non-shift deletion mutation, and Sanger sequencing showed that the mother, daughter, and cousin carried the same mutation. Conclusion:ENG gene c.579_ 599del mutation may be the genetic basis of HHT in this family.目的： 探讨ENG基因变异所致遗传性出血性毛细血管扩张症（hereditary hemorrhagic telangiectasia，HHT）一家系的遗传学特征。 方法： 选取在大理大学第一附属医院就诊的一个HHT家系3代共17人为研究对象。收集该HHT家系先证者的临床资料及家系患病情况。应用全外显子组测序技术对先证者进行疑似致病基因筛选，应用Sanger测序进行家系验证。 结果： 先证者及母亲有反复鼻出血、皮肤黏膜毛细血管扩张表现，先证者及其母亲、女儿和表弟胸部增强CT提示存在不同程度的肺动静脉畸形。全外显子测序结果显示先证者携带ENG基因c.579_599del非移码缺失突变，Sanger测序显示其母亲、女儿和表弟携带相同的变异。 结论：ENG基因c.579_599del突变可能是导致该家系HHT的遗传学基础。.
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Purpose To identify disease-causing mutations in a Chinese patient with retinitis pigmentosa (RP). Methods A detailed clinical examination was performed on the proband. Targeted next-generation sequencing (NGS) combined with bioinformatics analysis was performed on the proband to detect candidate disease-causing mutations. Sanger sequencing was performed on all subjects to confirm the candidate mutations and assess cosegregation within the family. Results Clinical examinations of the proband showed typical characteristics of RP. Three candidate heterozygous mutations in 3 genes associated with RP were detected in the proband by targeted NGS. The 3 mutations were confirmed by Sanger sequencing and the deletion (c.357_358delAA) in PRPF31 was shown to cosegregate with RP phenotype in 7 affected family members, but not in 3 unaffected family members. Conclusions The deletion (c.357_358delAA) in PRPF31 was the disease-causing mutation for the proband and his affected family members with RP. To our knowledge, this is the second report of the deletion and the first report of the other 2 mutations in the Chinese population. Targeted NGS combined with bioinformatics analysis proved to be an effective molecular diagnostic tool for RP.
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To explore the genetic basis of a proband with distinctive facial features, global developmental delay, seizures and hypoplasia of corpus callosum through next generation sequencing (NGS).Genomic DNA was extracted from peripheral blood samples of the proband and his family members. Whole exome and flanking sequences were screened by NGS. Suspected variants were verified by Sanger sequencing.The proband was found to carry a heterozygous c.2824G>T (p.G942X) variant of the ZEB2 gene, which was verified by Sanger sequencing to be a de novo variant.The heterozygous c.2824G>T (p.G942X) variant of the ZEB2 gene probably underlies the Mowat-Wilson syndrome in the proband.
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Homozygous familial hypercholesterolaemia (FH) is a rare disorder in which the patients develop severe hypercholesterolaemia and premature coronary atherosclerosis from childhood. Here we report a unique family with clustering of homozygous FH. The proband was a 25‐year‐old man, who showed marked hypercholesterolaemia, multiple xanthomas and severe coronary atherosclerosis. His mother also showed the typical characteristics of homozygous FH. Sequencing analysis of the low‐density lipoprotein receptor gene revealed that he was a compound heterozygote, carrying two different point mutations. One was a novel mutation, FH Wakayama (Cys→A Ser at 317), derived from his mother, and the other was a recurrent mutation, FH Niigata (T→A C at 1845+2, 5′ splice signal in intron 12), derived from his father. The proband we report seems to be a very rare case of an FH homozygote born from a homozygous mother.
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To explore the genetic basis for a patient with Familial hemophagocytic lymphohistiocytosis (FHL).A 35-day-old male infant who was admitted to the Oriental Hospital Affiliated to Xiamen University on August 3, 2021 due to fever for over 7 hours was selected as the study subject. Whole exome sequencing (WES) was carried out for the proband and his parents, and candidate variants were selected based on the clinical phenotypes of the proband and confirmed by Sanger sequencing.WES and Sanger sequencing results revealed that the proband had harbored compound heterozygous c.67_71delinsGCCC and c.65delC variants of the PRF1 gene, which were respectively inherited from his mother and father. The c.67_71delinsGCCC variant was unreported previously. Based on the guidelines of American College of Medical Genetics and Genomics and clinical manifestations, it was classified as pathogenic (PVS1+PM2_Supporting+PM3+PP4). c.65delC was a known pathogenic variant (PVS1+PM2_Supporting+PM3_Strong+PP4).The compound heterozygous variants of c.67_71delinsGCCC and c.65delC of the PRF1 gene probably underlay the disease in the proband. The identification of the novel variant has expanded the mutational spectrum of the PRF1 gene.
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To explore the genetic basis for a child featuring congenital insensitivity to pain (CIP).Targeted capture and next generation sequencing (NGS) was carried out for the proband. Suspected pathogenic variants were confirmed by Sanger sequencing of the proband and his parents.The proband was found to harbor compound heterozygous variants of SCN9A gene, namely c.1598delA (p.N533Ifs*31) and c.295_296delCGinsAT (p.R99I), which were respectively inherited from his father and mother. Both variants were predicted to be pathogenic, and neither was reported previously.The compound heterozygous variants of the SCN9A gene probably underlay the CIP in this child. Above finding has enabled genetic counseling for this family.
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To analyze the clinical characteristics and genetic features of a family affected with isolated proteinuria.Clinical data of the family was collected. Mutations of 191 renal disease-related genes in the proband were screened with next generation sequencing (NGS). Sanger sequencing was used to verify suspected mutations in his family members and 100 healthy controls. The impact of the mutation was predicted with online software SIFT. Frequency of the mutation was searched in databases including 1000 Genomic Project, ESP and ExAC.NGS and Sanger sequencing showed that the proband harbored compound heterozygous mutations of ADCK4 gene including c.748C>G (p.Asp250His) and c.1041G>T (p.Cys347*), which were respectively inherited from his mother and father whom were both non-symptomatic.The proband may have ADCK4-associated glomerulopathy due to the compound heterozygous mutations of the ADCK4 gene.
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