Dual primary gastric and colorectal cancer:The known hereditary causes and underlying mechanisms

In this editorial,I commented on the paper by Lin et al,published in this issue of the World Journal of Gastrointestinal Oncology.The work aimed at analysing the clinicopathologic characteristics and prognosis of synchronous and metachronous cancers in patients with dual primary gastric and colorectal cancer(CRC).The authors concluded the necessity for regular surveillance for metachronous cancer during postoperative follow-up and reported the prognosis is influenced by the gastric cancer(GC)stage rather than the CRC stage.Although surveillance was recommended in the conclusion,the authors did not explore this area in their study and did not include tests used for such surveillance.This editorial focuses on the most characterized gastrointestinal cancer susceptibility syndromes concerning dual gastric and CRCs.These include hereditary diffuse GC,familial adenomatous polyposis,hereditary nonpolyposis colon cancer,Lynch syndrome,and three major hamartomatous polyposis syndromes associated with CRC and GC,namely Peutz-Jeghers syndrome,juvenile polyposis syndrome,and PTEN hamartoma syndrome.Careful assessment of these syndromes/conditions,including inheritance,risk of gastric and colorectal or other cancer development,genetic mutations and recommended genetic investigations,is crucial for optimum management of these patients.

Genetically modified pigs:Emerging animal models for hereditary hearing loss

Hereditary hearing loss(HHL),a genetic disorder that impairs auditory function,significantly affects quality of life and incurs substantial economic losses for society.To investigate the underlying causes of HHL and evaluate therapeutic outcomes,appropriate animal models are necessary.Pigs have been extensively used as valuable large animal models in biomedical research.In this review,we highlight the advantages of pig models in terms of ear anatomy,inner ear morphology,and electrophysiological characteristics,as well as recent advancements in the development of distinct genetically modified porcine models of hearing loss.Additionally,we discuss the prospects,challenges,and recommendations regarding the use pig models in HHL research.Overall,this review provides insights and perspectives for future studies on HHL using porcine models.

Complex heterozygous mutations in hereditary spherocytosis:A case report

BACKGROUND The aim of this study was to investigate the complex heterozygous mutations of ANK1 and SPTA1 in the same individual and improve our understanding of hereditary spherocytosis(HS)in children.We also hope to promote the application of gene detection technology in children with HS,with the goals of identifying more related gene mutations,supporting the acquisition of improved molecular genetic information to further reveal the pathogenesis of HS in children,and providing important guidance for the diagnosis,treatment,and prevention of HS in children.CASE SUMMARY A 1-year and 5-month-old patient presented jaundice during the neonatal period,mild anemia 8 months later,splenic enlargement at 1 year and 5 months,and brittle red blood cell permeability.Genetic testing was performed on the patient,their parents,and sister.Swiss Model software was used to predict the protein structure of complex heterozygous mutations in ANK1 and SPTA1.Genetic testing revealed that the patient harbored a new mutation in the ANK1 gene from the father and a mutation in the SPTA1 gene from the mother.Combined with the clinical symptoms of the children,it is suggested that the newly discovered complex heterozygous mutations of ANK1 and SPTA1 may be the cause,providing important guidance for revealing the pathogenesis,diagnosis,treatment,and promotion of gene detection technology in children with HS.CONCLUSION This case involves an unreported complex heterozygous mutation of ANK1 and SPTA1,which provides a reference for exploring HS.

Hereditary polyposis syndromes remain a challenging disease entity:Old dilemmas and new insights

In this editorial we present an overview and insights of the management of hereditary polyposis syndromes.The primary focus was on familial adenomatous polyposis,juvenile polyposis syndrome and Peutz-Jegher syndrome.Genetic testing has become increasingly available and is easier than ever to integrate into clinical practice.Furthermore,several genes have been added to the expanding list of genes associated with hereditary polyposis syndromes,allowing for precise diagnostics and tailored follow-up.Endoscopic evaluation of patients with hereditary polyposis syndromes is paramount in the surveillance strategies.Current endoscopic procedures include both diagnostic procedures and surveillance as well as therapeutic interventions.Recommendations for endoscopic procedures in the upper and lower gastrointestinal canal were described.Surgery is still a key component in the management of patients with hereditary polyposis syndromes.The increased cancer risk in these patients often render prophylactic procedures or intended curative procedures in the case of cancer development.Surgical interventions in the upper and lower gastrointestinal canal were described with relevant considerations.Development of chemopreventive medications is ongoing.Few drugs have been investigated,including nonsteroidal anti-inflammatory drugs.It has been demonstrated that cyclooxygenase-2 inhibitors may lower the number of polyps.Other medications are currently under investigation,but none have,to date,consistently been able to prevent development of disease.

Decoding hereditary spastic paraplegia pathogenicity through transcriptomic profiling

Hereditary spastic paraplegia(HSP)is a group of genetic motor neuron diseases resulting from length-dependent axonal degeneration of the corticospinal upper motor neurons.Due to the advancement of next-generation sequencing,more than 70 novel HSP disease-causing genes have been identified in the past decade.Despite this,our understanding of HSP physiopathology and the development of efficient management and treatment strategies remain poor.One major challenge in studying HSP pathogenicity is selective neuronal vulnerability,characterized by the manifestation of clinical symptoms that are restricted to specific neuronal populations,despite the presence of germline disease-causing variants in every cell of the patient.Furthermore,disease genes may exhibit ubiquitous expression patterns and involve a myriad of different pathways to cause motor neuron degeneration.In the current review,we explore the correlation between transcriptomic data and clinical manifestations,as well as the importance of interspecies models by comparing tissue-specific transcriptomic profiles of humans and mice,expression patterns of different genes in the brain during development,and single-cell transcriptomic data from related tissues.Furthermore,we discuss the potential of emerging single-cell RNA sequencing technologies to resolve unanswered questions related to HSP pathogenicity.

Double heterozygous pathogenic mutations in KIF3C and ZNF513 cause hereditary gingival fibromatosis

Hereditary gingival fibromatosis(HGF)is a rare inherited condition with fibromatoid hyperplasia of the gingival tissue that exhibits great genetic heterogeneity.Five distinct loci related to non-syndromic HGF have been identified;however,only two diseasecausing genes,SOS1 and REST,inducing HGF have been identified at two loci,GINGF1 and GINGF5,respectively.Here,based on a family pedigree with 26 members,including nine patients with HGF,we identified double heterozygous pathogenic mutations in the ZNF513(c.C748T,p.R250W)and KIF3C(c.G1229A,p.R410H)genes within the GINGF3 locus related to HGF.Functional studies demonstrated that the ZNF513 p.R250W and KIF3C p.R410H variants significantly increased the expression of ZNF513 and KIF3C in vitro and in vivo.ZNF513,a transcription factor,binds to KIF3C exon 1 and participates in the positive regulation of KIF3C expression in gingival fibroblasts.Furthermore,a knock-in mouse model confirmed that heterozygous or homozygous mutations within Zfp513(p.R250W)or Kif3c(p.R412H)alone do not led to clear phenotypes with gingival fibromatosis,whereas the double mutations led to gingival hyperplasia phenotypes.In addition,we found that ZNF513 binds to the SOS1 promoter and plays an important positive role in regulating the expression of SOS1.Moreover,the KIF3C p.R410H mutation could activate the PI3K and KCNQ1 potassium channels.ZNF513 combined with KIF3C regulates gingival fibroblast proliferation,migration,and fibrosis response via the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK pathways.In summary,these results demonstrate ZNF513+KIF3C as an important genetic combination in HGF manifestation and suggest that ZNF513 mutation may be a major risk factor for HGF.

Clinical manifestations of adult hereditary spherocytosis with novel SPTB gene mutations and hyperjaundice:A case report

BACKGROUND The aim of the present study was to enhance understanding of the diagnosis and treatment of atypical hereditary spherocytosis(HS),and to broaden the diagnostic thoughts of physicians for patients with jaundice.CASE SUMMARY A 28-year-old male presented with jaundice,bile duct stone,and splenomegaly,but without anemia.Other causes of jaundice were excluded,and gene se-quencing revealed a novel heterozygous variant of c.1801C>T(p.Q601X)in exon 14 of the SPTB(NM_01355436)gene on chromosome 14(chr14:65260580)in the patient’s blood;the biological parents and child of the patient did not have similar variants.A splenectomy was performed on the patient and his bilirubin levels returned to normal after surgery.Thus,a novel gene variant causing HS was identified.This variant may result in the truncation ofβ-hemoglobin in the erythrocyte membrane,leading to loss of normal function,jaundice,and hemolytic anemia.The clinical manifestations of the patient were hyperjaundice and an absence of typical hemolysis during the course of the disease,which caused challenges for diagnosis by the clinicians.CONCLUSION Following a definitive diagnosis,genetic testing and response to treatment identified a gene variant site for a novel hemolytic anemia.

Photoreceptor changes in Leber hereditary optic neuropathy with m.G11778A mutation

·AIM:To evaluate the functional and structural changes of photoreceptors in patients and asymptomatic carriers with Leber hereditary optic neuropathy(LHON)using fullfield electroretinography(FERG)and optical coherence tomography(OCT).·METHODS:Individuals diagnosed with LHON at the Renmin Hospital of Wuhan University and their family members were included in this cross-sectional observational study.The FERG a-wave amplitude of affected patients and asymptomatic carriers was analyzed.The thickness of the outer nuclear layer(ONL),inner and outer segment(IS/OS)and total photoreceptors in the macular fovea and parafovea were measured.·RESULTS:This study included 14 LHON patients(mean age:20.00±9.37y),12 asymptomatic carriers(mean age:39.83±6.48y),and 14 normal subjects(mean age:24.20±1.52y).The FERG results showed that the darkadapted 3.0 electroretinography and light-adapted 3.0 electroretinography a-wave amplitudes of patients and carriers were significantly decreased(P<0.001).The ONL and photoreceptors layers were slightly thicker in patients than in normal subjects(P<0.05),whereas they were thinner in carriers(P<0.05).There were no differences in IS/OS thickness among the groups(P>0.05).·CONCLUSION:Photoreceptors function is significantly impaired in LHON-affected patients and asymptomatic carriers.Meanwhile,photoreceptors morphology is slightly altered,mainly manifesting as a change in ONL thickness.

Novel mutation of SPG4 gene in a Chinese family with hereditary spastic paraplegia:A case report

BACKGROUND Hereditary spastic paraplegia(HSP)is a group of neurogenetic diseases of the corticospinal tract,accompanied by distinct spasticity and weakness of the lower extremities.Mutations in the spastic paraplegia type 4(SPG4)gene,encoding the spastin protein,are the major cause of the disease.This study reported a Chinese family with HSP caused by a novel mutation of the SPG4 gene.CASE SUMMARY A 44-year-old male was admitted to our hospital for long-term right lower limb weakness,leg stiffness,and unstable walking.His symptoms gradually worsened,while no obvious muscle atrophy in the lower limbs was found.Neurological examinations revealed that the muscle strength of the lower limbs was normal,and knee reflex hyperreflexia and bilateral positive Babinski signs were detected.Members of his family also had the same symptoms.Using mutation analysis,a novel heterozygous duplication mutation,c.1053dupA,p.(Gln352Thrfs*15),was identified in the SPG4 gene in this family.CONCLUSION A Chinese family with HSP had a novel mutation of the SPG4 gene,which is autosomal dominant and inherited as pure HSP.The age of onset,sex distribution,and clinical manifestations of all existing living patients in this family were analyzed.The findings may extend the current knowledge on the existing mutations in the SPG4 gene.

Hereditary cancer syndromes

Hereditary cancer syndromes(HCSs)are arguably the most frequent category of Mendelian genetic diseases,as at least 2%of presumably healthy subjects carry highly-penetrant tumor-predisposing pathogenic variants(PVs).Hereditary breast-ovarian cancer and Lynch syndrome make the highest contribution to cancer morbidity;in addition,there are several dozen less frequent types of familial tumors.The development of the majority albeit not all hereditary malignancies involves two-hit mechanism,i.e.the somatic inactivation of the remaining copy of the affected gene.Earlier studies on cancer families suggested nearly fatal penetrance for the majority of HCS genes;however,population-based investigations and especially large-scale next-generation sequencing data sets demonstrate that the presence of some highly-penetrant PVs is often compatible with healthy status.Hereditary cancer research initially focused mainly on cancer detection and prevention.Recent studies identified multiple HCS-specific drug vulnerabilities,which translated into the development of highly efficient therapeutic options.

Chest wall osteochondroma resection with biologic acellular bovine dermal mesh reconstruction in pediatric hereditary multiple exostoses:A case report and review of literature

BACKGROUND Hereditary multiple exostoses is a rare genetic disorder characterized by the growth of multiple osteochondromas affecting primarily long bones.Chest wall lesions may represent a challenge,particularly in pediatric patients.Pain is a common manifestation.However,life-threatening complications can result from direct involvement of adjacent structures.Surgical resection with appropriate reconstruction is often required.CASE SUMMARY A 5-year-old male who was diagnosed with hereditary multiple exostoses presented with significant pain from a large growing chest wall exostosis lesion.After appropriate preoperative investigations,he underwent surgical resection with reconstruction of his chest wall using a biologic bovine dermal matrix mesh.CONCLUSION Resection of chest wall lesions in children represents a challenge.Preoperative planning to determine the appropriate reconstruction strategy is essential.

Hereditary hemorrhagic telangiectasia involving portal venous system:A case report and review of the literature

BACKGROUND Hereditary hemorrhagic telangiectasia(HHT)is an autosomal dominant genetic disorder with an incidence of approximately 1 in 5000 in the general population.It is characterized by vasodilation,which affects specific organs,such as the skin,mucous membranes,brain,lungs,gastrointestinal tract,liver,and others.However,HHT rarely involves the portal venous system to cause serious clinical compli-cations.CASE SUMMARY A 68-year-old woman was admitted to the emergency department due to four consecutive days of abdominal pain and bloody stool and was subsequently diagnosed with HHT.Computed tomography angiography confirmed the presence of an arteriovenous fistula(AVFs).Considering this specific manifestation,whole exome sequencing was performed.After a comprehensive evaluation,a selective superior mesenteric artery embolization was prioritized to avoid intestinal ischemia.The postoperative symptoms of the patient were quickly relieved.Unfortunately,two months post-procedure the patient died from intestinal necrosis and abdominal infection related to remaining AVFs.CONCLUSION For patients with diffuse superior mesenteric AVFs,selective mesenteric arterial embolization may lead to positive short-term outcomes.

Multi-organ hereditary hemorrhagic telangiectasia:A case report

BACKGROUND Type 2 hereditary hemorrhagic telangiectasia(HHT)is a rare autosomal dominant disease and is associated with ALK1 gene mutations.Type 2 HHT patients primarily suffer from recurrent bleeding.There is currently no promising treatment.CASE SUMMARY A 5-year-old Chinese patient(III23)was admitted to Zhongshan Hospital for recurrent melena occurring over 2 mo.She had been experiencing epistaxis for years and had been diagnosed with idiopathic pulmonary hypertension 4 mo before presentation.Abdominal computed tomography examination showed hepatic arteriovenous malformation.Gene testing revealed a c.1121G>A mutation on the ALK1 gene.According to the international diagnostic criteria,this patient was diagnosed with HHT.In addition,8 more family members exhibited HHT symptoms to varying degrees.Gene testing in 5 family members(2 with HHT symptoms and 3 without HHT symptoms)revealed the ALK1 c.1121G>A mutation in the 2 family members with HHT symptoms.This missense mutation results in the substitution of arginine for glutamine at amino acid position 374(R374Q)in the conserved functional kinase domain of ALK1.Biological studies revealed that this mutation decreased the kinase activity of ALK1 and impeded the phosphorylation of its substrate Smad1.Moreover,the R374Q mutant downregulated the protein level of collagen-1,a fibrogenic factor,indicating abnormal fiber generation during vascular formation.CONCLUSION The R374Q mutant of ALK1 and its subsequent influence on fiber generation highly indicated its pathogenic role in this family with type 2 HHT.Detection of this gene mutation will facilitate early diagnosis of suspected type 2 HHT patients,and mechanistic studies will provide insights for future therapy.

Hereditary Multiple Exostoses (HME) with Peroneal Nerve Compresion: A Case Report

Introduction: Hereditary multiple exostosis (HME) is a hereditary disorder characterized by multiple osteochondromas. Clinical symptoms can result from compression of adjacent structures such as peripheral nerves. In Indonesia, HME with nerve compression cases have rarely reported. Presentation of Case: An eleven-year-old female with complaining of left knee joint pain and progressive masses in left lower leg since 6 years ago. This complains followed by numbness and difficulty to dorso flexion motion on left ankle joint since four months ago. Physical examination showed of the bony masses was detected at the left lateral upper third lower leg with measuring about six into eight centimeters. Range of motion of left ankle joint patient had difficult to dorso flexion. X-ray imaging viewed demonstrates multiple exostosis appearance involving distal femoral, proximal fibula, proximal tibia and distal fibula bone. MR Imaging revealed cartilage cap of head fibula is thin less 1.5 cm and the axially specimen showed peroneal nerve compression. The patient underwent left head fibula wide resection. Intraoperative findings peripheral nerve peroneal compression and was decompression. Medical rehabilitation for physiotherapy was advised. The results of the follow-up after 2 years, no pain feels and the patient was able to dorso flexion of left ankle joint and no additional bumps in other areas of the body. These lesions may arise from any bone which was pre-formed in the cartilage. Nerve compression syndromes are the neurological complex symptom caused by the mechanical or dynamic compression of a specific single segment. MRI was excellent demonstration of blood vessels compromise and represents choices with peripheral nerves structures and to measuring cartilage cap thickness for criterion of osteochondromas differentiation and exostotic grade. Complete resection was importance of the cartilaginous cap to prevent recurrence. The decompressing the peroneal nerve that pressured by the masses and vascular problems occured. Conclusion: Hereditary multiple exostosis is an inherited disorder characterized by multiple osteochondromas. It is important to monitor all cases of HME especially if the patient complains of pain or growth of an osteochondroma. The surgical excision, with complete resection of the cartilaginous cap of the tumor, is important in preventing recurrence.

Hepcidin levels in hereditary hyperferritinemia:Insights into the iron-sensing mechanism in hepatocytes

AIM:To study the role of hepcidin in hereditary hyperferritinemia cataract syndrome(HHCS). METHODS:Six patients from two families with HHCS, confirmed by genetic analysis showing A to G mutation at position+40 in the L-ferritin gene,were recruited to undergo serum hepcidin and prohepcidin measurements using radioimmunoassay and enzyme linked immunoassay,respectively,and measurements were compared with levels in serum from 25 healthy volunteers(14 females),mean age 36±11.9 years.RESULTS:The serum hepcidin and prohepcidin levels in patients with HHCS were 19.1±18.6 and 187± 120.9 ng/mL,respectively.Serum ferritin was 1716.3± 376μg/L.Liver biopsy in one patient did not show any evidence of iron overload.Serum hepcidin and prohepcidin values in healthy controls(HCs)were 15.30±15.71 and 236.88±83.68 ng/mL,respectively,while serum ferritin was 110±128.08μg/L.There was no statistical difference in serum hepcidin level between the two cohorts(19.1±18.6 ng/mL vs 15.30±15.71 ng/mL,P= 0.612)using two-tailed t-test. CONCLUSION:Serum hepcidin levels in HHCS patients is similar to that in HCs.Our study suggests that circulating ferritin is not a factor influencing hepcidin synthesis and does not have a role in the iron-sensing mechanism in hepatocytes.

Stem Cell Ophthalmology Treatment Study (SCOTS)： bone marrow-derived stem cells in the treatment of Leber＇s hereditary optic neuropathy

The Stem Cell Ophthalmology Treatment Study （SCOTS） is currently the largest-scale stem cell ophthal- mology trial registered at ClinicalTrials.gov （identifier： NCT01920867）. SCOTS utilizes autologous bone marrow-derived stem cells （BMSCs） to treat optic nerve and retinal diseases. Treatment approaches include a combination of retrobulbar, subtenon, intravitreal, intra-optic nerve, subretinal, and intravenous injection of autologous BMSCs according to the nature of the disease, the degree of visual loss, and any risk factors related to the treatments. Patients with Leber＇s hereditary optic neuropathy had visual acuity gains on the Early Treatment Diabetic Retinopathy Study （ETDRS） of up to 35 letters and Snellen acuity improvements from hand motion to 20/200 and from counting fingers to 20/100. Visual field improvements were noted. Macular and optic nerve head nerve fiber layer typically thickened. No serious complications were seen. The increases in visual acuity obtained in our study were encouraging and suggest that the use of autolo- gous BMSCs as provided in SCOTS for ophthalmologic mitochondrial diseases including Leber＇s hereditary optic neuropathy may be a viable treatment option.

Germline mutation analysis of hPMS2 gene in Chinese families with hereditary nonpolyposis colorectal cancer

AIM: To study the germline mutation of hPMS2 gene in 26 unrelated Chinese hereditary nonpolyposis colorectal cancer (HNPCC) probands and to fulfill the screening strategy for HNPCC in Chinese. METHODS: Genomic DNA was extracted from the peripheral blood. To avoid the interference of pseudogene in detection of the remaining 11 exons (exon 1-5, 9, 11-15), long-range polymerase chain reaction (PCR) was conducted to amplify the complete coding region of hPMS2 gene firstly. Then 1/8 of the PCR productswere used as template to amplify the individual exon respectively and DNA sequencing was done. Direct DNA sequencing of the conventional PCR products of exon 6, 7, 8 and 10 of hPMS2 gene was performed. The same analysis was made in 130 healthy persons without family histories of HNPCC to further investigate the pathological effects of the detected missense mutation. RESULTS: One HNPCC proband fulf illed Bethesda guidelines and was found to carry the germline mutation of hPMS2 gene, which has not been reported in Chinese HNPCC families. It was a missense mutation at c.1532C>T of exon 11. It was detected in three controls as well with an occurrence rate of 2.3% (3/130). Since it could not be found in the PMS2-single nucleotide polymorphism (SNP) database, this missense mutation is a new SNP unreported up to date. Meanwhile, 260 reported SNPs of hPMS2 gene were detected in the 26 HNPCC probands. The 2nd and 5th exons were probably the hot SNP regions of hPMS2 gene in Chinese HNPCC families involving 53.1% of all reported SNP. CONCLUSION: The germline mutation of hPMS2 gene may be rare in Chinese HNPCC families. The 2nd and 5th exons are hot SNP regions of hPMS2 gene.

Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

Hereditary non-polyposis colorectal cancer(HNPCC) was previously synonymous with Lynch syndrome; however,identification of the role of germline mutations in the DNA mismatch repair(MMR) genes has made it possible to differentiate Lynch syndrome from other conditions associated with familial colorectal cancer(CRC). Broadly,HNPCC may be dichotomized into conditions that demonstrate defective DNA MMR and microsatellite instability(MSI) vs those conditions that demonstrate intact DNA MMR. Conditions characterized by MMR deficient CRCs include Lynch syndrome(germline MMR mutation),Lynch-like syndrome(biallelic somatic MMR mutations),constitutional MMR deficiency syndrome(biallelic germline MMR mutations),and sporadic MSI CRC(somatic biallelic methylation of MLH1). HNPCC conditions with intact DNA MMR associated with familial CRC include polymerase proofreading associated polyposis and familial colorectal cancer type X. Although next generation sequencing technologies have elucidated the genetic cause for some HNPCC conditions,others remain genetically undefined. Differentiating between Lynch syndrome and the other HNPCC disorders has profound implications for cancer risk assessment and surveillance of affected patients and their at-risk relatives. Clinical suspicion coupled with molecular tumor analysis and testing for germline mutations can help differentiate the clinical mimicry within HNPCC and facilitate diagnosis and management.

Hereditary diffuse gastric cancer: What the clinician should know

Hereditary diffuse gastric cancer(HDGC) is an inherited autosomal dominant syndrome with a penetrance of up to 80% affecting diverse geographic populations. While it has been shown to be caused mainly by germline alterations in the E-cadherin gene(CDH1), problematically, the genetic diagnosis remains unknown in up to 60% of patients. Given the important knowledge gaps regarding the syndrome, asymptomatic carriers of CDH1 mutations are advised for a prophylactic total gastrectomy. Intensive annual endoscopic surveillance is the alternative for carriers who decline gastrectomy. As HDGCs have a prolonged indolent phase, this provides a window of opportunity for surveillance and treatment. Recent findings of other gene defects in CTNNA1 and MAP3K6, as well as further characterization of CDH1 mutations and their pathogenicity will change the way HDGC patients are counselled for screening, surveillance and treatment. This review will bring the reader up to date with these changes and discuss future directions for research; namely more accurate risk stratification and surveillance methods to improve clinical care of HDGC patients.

Mitochondrial variants may influence the phenotypic manifestation of Leber's hereditary optic neuropathy-associated ND4 G11778A mutation

We report here the characterization of a five-generation Han Chinese family with Leber＇s hereditary optic neuropathy （LHON）. Strik- ingly, this Chinese family displayed high penetrance and expressivity of visual loss. The average age-of-onset of vision loss was 18 years in this family. Nineteen （11 males/8 females） of 29 matrilineal relatives in this family developed visual loss with a wide range of severity, ranging from blindness to normal vision. Sequence analysis of mitochondrial genome in this pedigree revealed the presence of the ND4 G 11778A mutation and 44 other variants belonging to Asian haplogroup M7b. The G 11778A mutation is present at homoplasmy in matri- lineal relatives of this Chinese family. Of other variants, the C01 G6480A, ND5 T12811C and Cytb A15395G located at highly conserved residues of corresponding polypeptides. In fact, these variants were implicated to be involved in other clinical abnormalities. Here, these variants may act in synergy with the primary LHON-associated Gl1778A mutation. Thus, the mitochondrial dysfunction caused by the primary ND4 G11778A mutation may be worsened by these mitochondrial variants. The results imply that the G6480A, T12811C and A15395G variants might have a potential modifier role in increasing the penetrance and expressivity of the primary LHON-associated G11778A mutation in this Chinese family.