Plasma biomarkers in patients with familial cavernous malformation and their first-degree relatives.

Background: We aimed to explore the differences in plasma biomarker levels between patients with familial cerebral cavernous malformations (FCCM) and their healthy first-degree relatives (FDRs) and between FCCM patients with and without severe chronic disease aggressiveness (CDA). Methods: Magnetic resonance imaging (MRI) scanning and genetic testing was performed in patients with multiple CCMs and their FDRs. Sixty-seven plasma biomarkers were tested using a customised multiplex bead immunoassay kit. Univariate and multivariate unconditional logistic regression analyses were conducted to determine the associations between plasma factors and the risk of developing FCCM and severe CDA. Receiver operating characteristic (ROC) curves were generated for each independent risk factor. Results: Plasma factors of 37 patients with FCCM and 37 FDRs were examined. Low CD31 (P < 0.001) and BDNF levels (P = 0.013) were independent risk factors for FCCM. The best model was achieved by combining the results of CD31 and BDNF (AUC = 0.845, sensitivity 0.838, specificity 0.784, cutoff score - 4.295) to distinguish patients with FCCM from healthy FDRs. Low serpin E1/PAI-1 (P = 0.011) and high ROBO4 levels (P = 0.013) were independent risk factors for severe CDA in patients with FCCM. The best model was achieved by combining the results of E1/PAI-1 and ROBO4 levels (AUC = 0.913, sensitivity 1.000, specificity 0.760, cutoff score - 0.525) to identify patients with FCCM and severe CDA. Conclusions: The plasma concentrations of CD31 and BDNF seem to be lower in patients with FCCM than in their healthy FDRs. Low serpin E1/PAI-1 and high ROBO4 concentrations may be correlated with high lesion burden and risk of recurrent bleeding.

A de novo ARIH2 gene mutation was detected in a patient with autism spectrum disorders and intellectual disability.

E3 ubiquitin protein ligase encoded by ARIH2 gene catalyses the ubiquitination of target proteins and plays a crucial role in posttranslational modifications across various cellular processes. As prior documented, mutations in genes involved in the ubiquitination process are often associated with autism spectrum disorder (ASD) and/or intellectual disability (ID). In the current study, a de novo heterozygous mutation was identified in the splicing intronic region adjacent to the last exon of the ARIH2 gene using whole exome sequencing (WES). We hypothesize that this mutation, found in an ASD/ID patient, disrupts the protein Ariadne domain which is involved in the autoinhibition of ARIH2 enzyme. Predictive analyses elucidated the implications of the novel mutation in the splicing process and confirmed its autosomal dominant inheritance model. Nevertheless, we cannot exclude the possibility that other genetic factors, undetectable by WES, such as mutations in non-coding regions and polygenic risk in inter-allelic complementation, may contribute to the patient's phenotype. This work aims to suggest potential relationship between the detected mutation in ARIH2 gene and both ASD and ID, even though functional studies combined with new sequencing approaches will be necessary to validate this hypothesis.

Uncovering an Unusual FBN1 Gene Mutation Responsible for Marfan Syndrome: A Case Study.

Patients with Marfan syndrome have a constellation of clinical features and a heterogeneous phenotype. The purpose of this study is to report a 47-year-old male patient with an unusual variant in the FBN1 gene causing Marfan syndrome. The patient with musculoskeletal, cardiovascular, and ocular findings compatible with Marfan syndrome had an unusual pathogenic mutation on the FBN1 gene. The patient was examined by at least one of the authors (NJI). The patient's clinical findings were compatible with Marfan syndrome. Our patient had a unique mutation in the FBN1 gene (c.8054A>G p.His2685Arg) located on exon 65. Next-generation sequencing was done using the Invitae panel. This variant was categorized as one of uncertain significance. This patient's variant on the FBN1 gene leading to the syndrome has scant data associated with it and this is the first time it is reported from Puerto Rico.

Gap Junction Beta-2 p.Val84Met Can Cause Autosomal Dominant Syndromic Hearing Loss With Keratoderma.

In this study, we report a case of bilateral mild hearing loss and keratoderma caused by a gap junction beta-2 (GJB2) variant. The proband was a nine-year-old Japanese boy with bilateral mild hearing loss at birth. The proband's father, sister, paternal aunt, and cousins had mild sensorineural hearing loss. Further evaluation revealed keratoderma on the feet of the proband, father, sister, paternal aunt, and cousins. We identified a heterozygous c.250G>A (p.Val84Met) variant in GJB2 as the cause of the autosomal dominant syndromic hearing loss with the skin disorder in this Japanese family and delineated the pathological significance of the variant. The Val84Met variant in GJB2 contributes to the autosomal dominant form of syndromic hearing loss with keratoderma.

The CAPN3 p.Lys 254del variant is not always associated with dominant CAPN3-related muscular dystrophy.

INTRODUCTION/AIMS: Limb-girdle muscular dystrophy R1 (LGMDR1) calpain 3-related usually presents as a recessively transmitted weakness of proximal limb-girdle muscles due to pathogenic variants in the CAPN3 gene. Pathogenic variants in this gene have also been found in patients with an autosomal dominantly inherited transmission pattern (LGMDD4). The mechanism underlying this difference in transmission patterns has not yet been elucidated. Camptocormia, progressive limb weakness, myalgia, back pain, and increased CK levels are common clinical features associated with dominant forms. The p.Lys254del pathogenic variant was associated with camptocormia in two LGMDD4 families. This study aimed to present carriers found in recessively transmitted LGMDR1 families bearing the p.Lys254del variant that do not show muscle weakness. METHODS: DNA sequencing was performed on exon 5 of CAPN3 in family members to establish the carrier status of the pathogenic variant. They were evaluated clinically and MRI was performed when available. RESULTS: Two families presented with the p.Lys254del pathogenic variant in a homozygous or compound heterozygous state. Family members carrying only the pathogenic variant in the heterozygous state did not demonstrate the myopathic characteristics described in dominant patients. Camptocormia and other severe clinical symptoms were not observed. DISCUSSION: We conclude that the p.Lys254del pathogenic variant per se cannot be solely responsible for camptocormia in dominant patients. Other undisclosed factors may regulate the phenotype associated with the dominant inheritance pattern in CAPN3 pathogenic variant carriers.

Prevalence and phenotypes associated with ALPK3 null variants in a large French multicentric cohort: Confirming its involvement in hypertrophic cardiomyopathy.

Biallelic disease-causing variants in the ALPK3 gene were first identified in children presenting with a severe cardiomyopathy. More recently, it was shown that carriers of heterozygous ALPK3 null variants are at risk of developing hypertrophic cardiomyopathy (HCM) with an adult onset. Since the number of reported ALPK3 patients is small, the mutational spectrum and clinical data are not fully described. In this multi-centric study, we described the molecular and clinical spectrum of a large cohort of ALPK3 patients. Genetic testing using targeted next generation sequencing was performed in 16 183 cardiomyopathy index cases. Thirty-six patients carried at least one null ALPK3 variant. The five paediatric patients carried two ALPK3 variants, all presented an HCM phenotype with severe outcomes (one transplantation, one heart failure and one cardiac arrest). The 31 adult patients carried heterozygous variants and the main phenotype was HCM (n = 26/31); including 15% (n = 4) presented with an apical or a concentric form of hypertrophy. Reporting a large cohort of ALPK3 patients, this collaborative work confirmed a strong association with HCM and suggesting his screening in the context of idiopathic HCM.

A novel mutation in the LRSAM1 gene in a family with early onset autosomal dominant Charcot-Marie-Tooth type 2P.

Charcot-Marie-Tooth disease type 2P (CMT2P; MIM #614436) is a specific type of axonal neuropathy caused by mutations in the LRSAM1 gene, which is a RING-type E3 ubiquitin ligase. CMT2P can be inherited in two ways: as an autosomal dominant or autosomal recessive trait. In this report, we describe the clinical characteristics of a family with axonal sensory-motor neuropathy caused by a new variant of the LSRAM1 gene, which is associated with early-onset autosomal dominant CMT2P.

Deciphering the pathogenicity of COL4A4 heterozygous splicing mutations and the genotype-phenotype correlation in autosomal dominant Alport syndrome / 中华肾脏病杂志

Objective:Through the investigation of the pathogenicity of COL4A4 heterozygous splicing mutations and the genotype-phenotype correlation in autosomal dominant Alport syndrome (ADAS), to better understand the impact of COL4A4 heterozygous splicing mutations on ADAS. Methods:The study was a case series analysis. Patients from 5 ADAS families with COL4A4 heterozygous splicing mutations detected by whole exome sequencing were recruited by three hospitals. In vivo transcriptional analysis and/or in vitro minigene splicing assay were conducted to determine the splicing patterns and assess the pathogenicity of COL4A4 heterozygous splicing mutations. Results:In the five ADAS pedigrees carrying COL4A4 heterozygous splicing mutations, four novel ADAS splicing patterns were described. In pedigree 1-4, most patients presented with continuous hematuria or/and microalbuminuria. Otherwise,the proband in pedigree 4 presented with macroalbuminuria and the proband in pedigree 1 had progressed to chronic kidney disease stage 2 at the age of 70 years old. In pedigree 5, all patients developed end-stage renal disease between 28 and 41 years old. c.735+3A>G detected in pedigree 1 and pedigree 2 and c.694-1G>C detected in pedigree 3 both led to exon 12 skipping in COL4A4, resulting in 42 nucleotides in-frame deletion (c.694_735del). c.2056+3A>G detected in pedigree 4 led to COL4A4 exon 26 skipping, which caused in-frame deletion of 69 nucleotides (c.1988_2056del). c.2716+5G>T detected in pedigree 5 led to a 360 nucleotides large in-frame deletion, including 100 bp sequence at the 3'end of exon 29,the whole sequence of exon 30 and 89 bp sequence at the 5'end of exon 31 (c.2446_2805del). Conclusions:Renal prognosis differs significantly for patients with small in-frame deletions versus large in-frame deletion splicing abnormalities. Determination of the pathogenicity and the splicing patterns of COL4A4 heterozygous splicing mutations using in vivo and in vitro transcriptional analysis may provide renal prognostic information.

Progress in the research and theranostics of neurofibromatosis type Ⅰ / 肿瘤

Neurofibromatosis type 1 is a progressive autosomal dominant inherited disease caused by a mutation in neurofibromin 1(NF1)gene located on chromosome 1 7q1 1.2.NF1 can cause systemic peripheral neuropathy,but the clinical manifestations are varied due to the different onset times and lesion sites in different patients.The treatment of NF1 involves multiple disciplines due to different lesion sites.Clinical monitoring and symptomatic treatment are the main methods for NF1 management,while radical treatment is difficult.New drugs targeted at the pathogenic gene-related signaling pathways are expected to improve the therapeutic effect for NF1.This review summarizes the progress in the basic research and clinical diagnosis and treatment of NF1.

Cleidocranial dysplasia: a case report and gene mutation analysis.

Cleidocranial dysplasia is a rare autosomal dominant hereditary disease that mainly affects the skeletal and dental development and has an incidence rate of about 1∶1 000 000. In this study, a case of cranio-clavicular dysplasia was reported, and related literature was reviewed. RUNX2 6p21.1 NM_001024630.3 Exon4 c.534dupAp.(Val179fs) was identified to be a new frameshift mutation by gene analysis.

Genotype and phenotype analysis of children with autosomal dominant inheritance Alport syndrome / 中华实用儿科临床杂志

Objective:To analyze the clinicopathological and gene mutation characteristics of children with autosomal dominant inheritance Alport syndrome (ADAS), and to improve the understanding of ADAS.Methods:Ten children with ADAS diagnosed in the Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology from September 2016 to February 2020 were enrolled.The clinicopathological and gene mutation features were retrospectively analyzed, and the patients were followed up.Results:(1) The median age at diagnosis was 5.7 (2.4, 9.8) years.Of 10 children, 6 cases (60.0%) showed a family history of renal failure, 4 cases (40.0%) presented with hematuria and proteinuria at diagnosis, and 2 cases (20.0%) suffered a high-frequency hearing loss.Renal biopsy showed extensive splitting and lamellation of the glomerular basement membrane (GBM) dense layer in 4 cases (40.0%), and segmental splitting and lamellation in 6 cases (60.0%). (2)Among 10 children, 4 cases (40.0%) were heterozygous mutations of COL4A3 gene, including 2 point mutations of glycine, and 2 splicing mutations.The other 6 cases (60.0%) were heterozygous mutations of COL4A4 gene, including collagen glycine point mutations in 4 cases, nonsense mutation in 1 case and large deletion in 1 case.Six mutations were new and never reported before. Conclusions:The early clinical presentations of children with ADAS are often atypical and extrarenal manifestations are less common.The GBM dense layer is mainly featured by segmental splitting and lamellation.Glycine point mutations account for the majority of the gene mutations.

Clinical characteristics and gene analysis of a family with autosomal dominant Alport syndrome with the onset of nephrotic syndrome / 中华实用儿科临床杂志

The clinical characteristics, mutation analysis results, and family tree of a patient with autosomal dominant Alport syndrome (ADAS), who had nephrotic syndrome as the first manifestation were examined.The proband was a 11-month-old girl who presented with nephrotic syndromes and gross hematuria.During the treatment course, the patient had steroid resistance and a poor response to Cyclosporine and Cyclophosphamide pulse therapy.Renal biopsy was performed 2 years after disease onset.Under the light microscopy, glomerular segmental mesangio-proliferative lesions were observed.The staining of type Ⅳ collagen showed the loss of the α3 chain in the glomerular basement membrane (GBM) and tubular basement membrane, and α5 chain loss in GBM.Electron microscopy showed uneven thickness of GBM, with obviously delaminated and tearing dense basement membrane (BM) layer, showing a typical lace-like change.The segmental BM was loosened and widened.Her father did not develop microscopic hematuria until 10 years later, while her grandmother had asymptomatic hematuria and proteinuria when the proband was diagnosed.A new mutation in the COL4A4 gene was found in the proband, namely c. 1715delG (p.G572Vfs * 81). Her father and grandmother carried the same mutation, but her mother and sister did not have.The clinical manifestation of ADAS is clinically heterogeneous and its incidence may be higher than what we have expected.

Characteristics of autosomal dominant retinal diseases and gene therapy strategies / 中华实验眼科杂志

Inherited retinal diseases (IRDs), one type of the major eye diseases resulting in blindness, can be caused by more than 270 identified causative genes.The most common form of IRDs is retinitis pigmentosa.There is no generally accepted cure for vision impairment due to IRDs.In recent years, the first gene replacement therapy has been approved for the treatment of autosomal recessive IRDs.Because of the variety of pathogenesis, including gain-of-function and dominant-negative effects in addition to a few loss-of-function mutations, gene replacement therapy of autosomal dominant IRDs is not always effective.The clinical manifestations of autosomal dominant IRDs are extremely complex, and there is no appropriate treatment in clinical practice.The latest progresses in pathogenesis, clinical features, treatment strategies and directions of autosomal dominant IRDs globally were reviewed, and the most common genes causing autosomal dominant IRDs were summarized in this article in order to provide a deeper understanding of autosomal dominant IRDs.

Basal cell nevus syndrome: 4 case reports and a literature review / 口腔疾病防治

Objective@#To summarize the incidence, clinical manifestations, diagnosis and treatment of basal cell nevus syndrome and to provide reference for clinical diagnosis and treatment. @*Methods @# Retrospective analysis of 4 cases of basal cell nevus syndrome admitted to the General Hospital of PLA during January 2017 to January 2018 and recent cases reported in the literature.@* Results@#In this study, 1 males and 3 females were included. The patients included a mother and her child. All 4 cases were surgically resected. Pathological reports included all keratocysts of the jaws. There has been no recurrence since follow-up. Through literature summarization and analysis, the clinical manifestations of this syndrome were found to be diverse. Typical clinical manifestations include multiple keratocysts of the jaws, multiple blepharospasms or cancers, deformities of the spine or ribs, increased brachial distance, eye diseases or special face intracranial calcification.@*Conclusion @#Basal cell nevus syndrome is an autosomal dominant genetic disorder. The clinical manifestations are diverse and the diagnosis is often overlooked. The incidence of cysts in the jaws is one of the important clinical manifestations of this syndrome. Early diagnosis and proper treatment improve patient survival and quality of life.

Clinical data and mutation analysis of two cases of CHARGE syndrome / 中华内分泌代谢杂志

Objective To analyze the clinical manifestations and possible gene mutation sites of Chinese patients in order to improve the clinician's understanding of CHARGE syndrome. Methods Clinical data were collected and blood samples were obtained from the proband of CHARGE syndrome and their relatives. The peripheral blood DNA was extracted and sequenced by PCR amplification. Mutation sites were verified by Sanger sequencing. Results For the first proband, a heterozygous mutation was detected in the intron 10 of CHD7 gene. His parents and brother did not have mutation. For the second proband, total repeat sequence in exon 7 of CHD7 gene was detected. His father carried the same mutation and his mother did not have mutation. Conclusion For the patients who are diagnosed with CHARGE syndrome based on the clinical manifestations, genetic mutation detection should be proceeded. It is useful for studying possible genetic pathogenesis and enhancing the awareness of clinicians.

Cleidocranial dysplasia: a case report and gene mutation analysis / 华西口腔医学杂志

Cleidocranial dysplasia is a rare autosomal dominant hereditary disease characterized by abnormal skeletal and dental development. In this work, a case of cleidocranial dysplasia is reported, and a new frameshift mutation is confirmed by gene detection.

Familial misophonia or selective sound sensitivity syndrome: evidence for autosomal dominant inheritance? / Misofonia familiar ou síndrome da sensibilidade seletiva a sons: evidência de herança autossômica dominante?

Abstract Introduction: Misophonia is a recently described, poorly understood and neglected condition. It is characterized by strong negative reactions of hatred, anger or fear when subjects have to face some selective and low level repetitive sounds. The most common ones that trigger such aversive reactions are those elicited by the mouth (chewing gum or food, popping lips) or the nose (breathing, sniffing, and blowing) or by the fingers (typing, kneading paper, clicking pen, drumming on the table). Previous articles have cited that such individuals usually know at least one close relative with similar symptoms, suggesting a possible hereditary component. Objective: We found and described a family with 15 members having misophonia, detailing their common characteristics and the pattern of sounds that trigger such strong discomfort. Methods: All 15 members agreed to give us their epidemiological data, and 12 agreed to answer a specific questionnaire which investigated the symptoms, specific trigger sounds, main feelings evoked and attitudes adopted by each participant. Results: The 15 members belong to three generations of the family. Their age ranged from 9 to 73 years (mean 38.3 years; median 41 years) and 10 were females. Analysis of the 12 questionnaires showed that 10 subjects (83.3%) developed the first symptoms during childhood or adolescence. The mean annoyance score on the Visual Analog Scale from 0 to 10 was 7.3 (median 7.5). Individuals reported hatred/anger, irritability and anxiety in response to sounds, and faced the situation asking to stop the sound, leaving/avoiding the place and even fighting. The self-reported associated symptoms were anxiety (91.3%), tinnitus (50%), obsessive-compulsive disorder (41.6%), depression (33.3%), and hypersensitivity to sounds (25%). Conclusion: The high incidence of misophonia in this particular familial distribution suggests that it might be more common than expected and raises the possibility of having a hereditary etiology.

Resumo Introdução: A misofonia é uma condição recentemente descrita, mal compreendida e negligenciada. É caracterizada por fortes reações negativas de ódio, raiva ou medo quando os indivíduos precisam enfrentar alguns sons repetitivos seletivos e de baixa intensidade. Os mais comuns que desencadeiam tais reações aversivas são aqueles provocados pela boca (mascar goma ou mastigar comida, estalar os lábios) ou nariz (respirando, cheirando e soprando) ou pelos dedos (digitando, amassando papel, clicando a caneta, tamborilando na mesa). Artigos anteriores citam que esses indivíduos geralmente conhecem pelo menos um parente próximo com sintomas semelhantes, sugerindo um possível componente hereditário. Objetivo: Encontramos e descrevemos uma família com 15 membros com misofonia, detalhando suas características comuns e o padrão de sons que desencadeiam um desconforto tão forte. Método: Todos os 15 membros concordaram em nos fornecer seus dados epidemiológicos e 12 concordaram em responder a um questionário específico que investigou os sintomas, sons de gatilho específicos, principais sentimentos evocados e atitudes adotadas por cada participante. Resultados: Os 15 membros pertencem a três gerações da família. A idade variou de 9 a 73 anos (média de 38,3 anos, mediana de 41 anos) e 10 eram mulheres. A análise dos 12 questionários mostrou que 10 indivíduos (83,3%) desenvolveram os primeiros sintomas durante a infância ou a adolescência. A média do escore de irritação na Escala Visual Analógica de 0 a 10 foi de 7,3 (mediana 7,5). Os indivíduos relataram sentimentos de ódio/raiva, irritabilidade e ansiedade em resposta a sons, e enfrentaram a situação pedindo para interromper o som, deixando/evitando o lugar e até mesmo discutindo. Os sintomas associados auto-relatados foram ansiedade (91,3%), zumbido (50%), transtorno obsessivo-compulsivo (41,6%), depressão (33,3%) e hipersensibilidade aos sons (25%). Conclusão: A alta incidência de misofonia nessa distribuição familiar em particular sugere que possa ser mais comum do que o esperado e suscita a possibilidade de haver uma etiologia hereditária.

Clinical characteristics of X-linked infantile nystagmus in a Chinese family / 上海交通大学学报（医学版）

Objective • To identify the clinical features of a Chinese Han family with X-linked infantile nystagmus. Methods • A Chinese family with X-linked infantile nystagmus was recruited from Department of Ophthalmology in Xinhua Hospital, Shanghai Jiao Tong University School of Medicine. Peripheral blood from the members of the family was collected and molecular genetic analysis was done. The 5 patients in the family received comprehensive ocular examinations including measurement of visual acuity, degree of anomalous head posture, stereoscopic vision, binocular function, electroretinogram, visual evoked potential, optical coherence tomography, eye movement recording and cycloplegic refraction. Results • A frame-shift mutation (c.823-829delACCCTAC, p.Thr275fs) in the 9th exon of FERM domain containing protein 7 (FRMD7) in the family was found. The similar clinical features of the family included moderate impairment of visual acuity, mild astigmatism, reduced stereoscopic vision, no fusion function, and bidirectional jerk wave form. Their electroretinograms were normal, but there was a peak latency and decreased amplitudes in visual evoked potential. And the structures of maculae had no obvious abnormality. The performance of the anomalous head posture was varied. Conclusion • Thr275fs in FRMD7 protein is identified as the main factor in the Chinese family with X-linked infantile nystagmus. The clinical features of the family show a certain degree of consistency.

Estudio dínico y molecular en una familia con displasia ectodermica hipohidrotica autosomica dominante / Clinical and molecular study in a family with autosomal dominant hypohidrotic ectodermal dysplasia

La displasia ectodérmica hipohidrótica (DEH) es una entidad infrecuente caracterizada por deficiencia en el desarrollo de estructuras derivadas del ectodermo y es causada por mutaciones en los genes EDA, EDAR o EDARADD, que pueden exhibir hallazgos clínicos similares, debido a una vía de señalización común. Las mutaciones en el gen EDA causan la DEH ligada al X, que es la forma más frecuente. Por su parte, las mutaciones en los genes EDAR y EDARADD causan la DEH con patrón de herencia autosómica dominante y recesiva. Los hallazgos clínicos más resaltantes son hipodoncia, hipotricosis e hipohidrosis, que pueden llevar a episodios de hipertermia. Se presentan los hallazgos clínicos en un niño con DEH con patrón de herencia autosómica dominante, cuyo análisis molecular demostró mutación heterocigótica c.1072C>T (p.Arg358X) en el gen EDAR, y se discuten los diferentes aspectos clínicos encontrados en esta mutación en los casos descritos en la literatura.

Hypohidrotic ectodermal dysplasia (HED) is a rare disease characterized by deficiency in development of structure derived from the ectoderm and is caused by mutations in the genes EDA, EDAR, or EDARADD. Phenotypes caused by mutations in these three may exhibit similar clinical features, explained by a common signaling pathway. Mutations in EDA gene cause X linked HED, which is the most common form. Mutations in EDAR and EDARADD genes cause autosomal dominant and recessive form of HED. The most striking clinical findings in HED are hypodontia, hypotrichosis and hypohidrosis that can lead to episodes of hyperthermia. We report on clinical findings in a child with HED with autosomal dominant inheritance pattern with a heterozygous mutation c.1072C>T (p.Arg358X) in the EDAR gene. A review of the literature with regard to other cases presenting the same mutation has been carried out and discussed.

Genetic localization and clinical classification of congenital fibrosis of the extraocular muscles in 2 Chinese families / 眼科新进展

Objective To determine the pathogenic mutant gene and the classification for 2 Chinese families with congenital fibrosis of the extraocular muscles (CFEOM) by using candidate genes methods.Methyls All members in the 2 Chinese families with CFEOM were collected and underwent for clinical data collection,including medical history,physical examination and 5-8 mL peripheral venous blood for DNA extraction.Exon 2,8,20,21 of KIF21A,exon 1,2,3 of PHOX2A/ARIX,exon 1,2,3,and 4 of TUBB2B and exon 1,2,3,4 of TUBB3 were selected and synthesized by PCR,and the amplified samples were purified for sequences analysis by Chromas2.3 and DNAman7.0 software.Results There were 9 members developed CFEOM in family 1,with the typical CFEOM characteristics.The mutation site was located in KIF21A (exon 21),2860C ＞ T;and 4 patients in family 2 suffered this disease,and the typical CFEOM appearance features was in 3 patients.The mutation site was located in TBUU3 (exon 4),1249 G ＞ A.Conclusion The candidate genes methods can be used to identify the pathogenic genes of pedigrees with inherited diseases effectively.Family 1 belongs to CFEOM 1A type,which is the autosomal dominant inheritance with complete penetrance,and family 2 belongs to CFEOM 3A type,whivh is the autosomal dominant inheritance with incomplete penetrance.