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Purpose: Ocular albinism type I (OA1) is caused by mutations in the GPR143 gene. The purpose of this study was to describe the clinical and genetic findings in 13 patients from 12 unrelated Chinese pedigrees with a pathogenic variant of the GPR143 gene., Methods: Most patients underwent clinical examination, including best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, fundus examination, spectral domain optical coherence tomography, and full-field electroretinograms (ERG). A combination of molecular screening procedures, consisting of Sanger-DNA sequencing of GPR143 and targeted next-generation sequencing, was performed to identify each mutation. In silico programs were utilized to evaluate the pathogenicity of all the variants., Results: The 13 patients (mean age 21.75 ± 16.63 years, range 1-54 years) all presented with congenital nystagmus, different extents of visual impairment, and severe foveal hypoplasia. Their BCVA was between 0.05 and 0.3 (decimal notation). The patients and obligate carriers exhibited different extents of mild depigmentation of the iris and fundus. We detected 11 distinct mutations in this patient cohort, including 7 novel mutations. Most (82%) were null mutations and included frameshift indel, nonsense, splicing effect, and large genomic DNA deletions, while missense mutations only accounted for 18%., Conclusions: Patients with GPR143 mutations all have congenital nystagmus, visual impairment, and foveal hypoplasia, whereas hypopigmentation in their iris and fundus is mild. They exhibit no evident genotype-phenotype correlations. GPR143 mutation screening is very important for establishing a precise diagnosis and for providing genetic counseling for patients and their families.

Background: Idiopathic infantile nystagmus (IIN) is a high genetically heterogeneous ophthalmic disease and is often associated with pathogenic mutations in FRMD7 and GPR143, respectively. Idiopathic infantile nystagmus manifests as involuntary periodic rhythmic oscillation of the eyes in the very early life, which decreases visual acuity and affects the quality of life., Objective and Methods: The aim of our study was to reveal a possible pathogenic variant through the investigation of a Chinese Han family with IIN with an implementation of a next-generation sequencing method. Isolated DNA analysis was followed by Sanger sequencing validation. We also performed the detailed ophthalmological examination of family members., Results: We identified a novel frameshift variant in FRMD7 (NM_194277.2: c.1419_1422dup, p.Tyr475fs), which leads to a frameshift mutation since tyrosine (Tyr) at 475 codon of FRMD7 protein (p.Tyr475fs) and co-segregates with IIN phenotype in this family., Conclusions: We found a novel frameshift FRMD7 variant in a Chinese Han family, which may be causative variant for IIN and can further enrich the mutation spectrum and uncover the etiology of IIN., (© 2019 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, Inc.)

Background: Hereditary spastic paraplegia (HSP) refers to a group of neurodegenerative disorders characterized by bilateral weakness, spasticity, and hyperreflexia in the lower limbs. The autosomal dominant HSP (ADHSP) predominantly presents as the pure form, but the clinical profiles and causal genetic variants underlying ADHSP are complex, and many remain unknown., Methods: A cohort of 15 Chinese HSP pedigrees (including 35 patients and their 22 relatives) were screened by multiplex ligation-dependent probe amplification (MLPA) or whole-exome sequencing (WES). Neurological assessments were also conducted., Results: The main subtypes of HSP above detected in our cohort were SPG4, SPG3A, and SPG6. Fifteen HSP-inducing mutations were identified, among which six were novel mutations: SPAST c.1277T>C, c.1292G>C, c.1562T>C, and c.1693A>T, NIPA1 c.748A>C, and KIDINS220 c.4448C>G. As expected, the most common presentation of the ADHSP cases was the pure form, manifesting spasticity of lower limbs and hyperreflexia, as well as pyramidal signs. Differing substantially from previous reports for KIDINS220 variants, our study family exhibited autosomal dominant inheritance, and only presented with spastic paraplegia, with no signs of intellectual disability, nystagmus, or obesity., Conclusion: Our work reveals a non-classical spastic paraplegia, intellectual disability, nystagmus, and obesity phenotype for a KIDINS220 mutation, which broadens both the clinical and genetic spectrum for ADHSP. Beyond underscoring the utility of using both MLPA and WES in studies of HSP, our work deepens the scientific understanding of phenotypes for ADHSP and defines new genetic variants to facilitate future diagnoses.

Background: Infantile nystagmus (IN) is an oculomotor disorder that is characterized by conjugate involuntary, rapid and repetitive movement of the eyes. To date, the pathogenesis of IN remains unclear. Many patients show an X-linked inheritance pattern. In this study, we explored the mutation in the FERM domain-containing 7 (FRMD7) gene in a Chinese family with X-linked infantile nystagmus., Methods: We conducted comprehensive ocular examinations and collected 5 ml of blood samples from members of a family with X-linked IN and 100 normal controls. Mutations in FRMD7 were identified by sequencing PCR products., Results: We found a 7-bp deletion(c.823-829delACCCTAC) in the 9th exon of FRMD7 in a Chinese family with IN, which predicted a truncation of the protein., Conclusions: This study reported a novel mutation of the FRMD7 gene occurred in a Chinese family with IN, thus expanding the spectrum of FRMD7 mutations causing IN, and further confirming that the mutations of FRMD7 are the underlying molecular cause of IN.

The purpose of the current study was to identify novel mutations in the FRMD7 (FERM domain containing 7) gene and to characterize clinical features in Chinese patients with congenital motor nystagmus. For this purpose, 18 patients with congenital motor nystagmus were selected from the ocular genetic diseases bank of the Pediatric and Genetic Clinic of Zhongshan Ophthalmic Center (Guangdong, China). Direct sequencing was used to analyze the exons and adjacent introns of the FRMD7 gene. The heteroduplex‑single strand conformation polypeptide method was used to analyze 96 unrelated normal controls and gene‑screening positive patients. Slit lamp photography of the anterior segment, fundus photography, optical coherence tomography and electroretinogram were carried out to identify the clinical features of congenital motor nystagmus. The authors noted that in, 18 patients with congenital motor nystagmus, there were 7FRMD7 gene mutations (six new mutations). The screening rate was 38.89%, including c.41_43delAGA (p.13‑15delK); c.473T>A (p.I158N); c.605T>A (p.I202N); c.580G>T (p.A194S); c.811T>A (p.C271S); c.1493insA (p.Y498X); c.57+1G>A (slice mutation). There were no such mutations in the 96 normal controls. These results enriched the gene mutation spectrum of FRMD7. The authors systematically investigated the clinical phenotype of congenital motor nystagmus in a Chinese population. The study provides further evidence for clinical diagnosis and differential diagnosis and genetic counseling.

Objectives: Infantile nystagmus (IN) is a genetically heterogeneous condition characterised by involuntary rhythmic oscillations of the eyes accompanied by different degrees of vision impairment. Two genes have been identified as mainly causing IN: FRMD7 and GPR143. The aim of our study was to identify the genetic basis of both sporadic IN and X-linked IN., Design: Prospective analysis., Patients: Twenty Chinese patients, including 15 sporadic IN cases and 5 from X-linked IN families, were recruited and underwent molecular genetic analysis. We first performed PCR-based DNA sequencing of the entire coding region and the splice junctions of the FRMD7 and GPR143 genes in participants. Mutational analysis and co-segregation confirmation were then performed., Setting: All clinical examinations and genetic experiments were performed in the Eye Hospital of Wenzhou Medical University., Results: Two mutations in the FRMD7 gene, including one novel nonsense mutation (c.1090C>T, p.Q364X) and one reported missense mutation (c.781C>G, p.R261G), were identified in two of the five (40%) X-linked IN families. However, none of putative mutations were identified in FRMD7 or GPR143 in any of the sporadic cases., Conclusions: The results suggest that mutations in FRMD7 appeared to be the major genetic cause of X-linked IN, but not of sporadic IN. Our findings provide further insights into FRMD7 mutations, which could be helpful for future genetic diagnosis and genetic counselling of Chinese patients with nystagmus., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The ocular albinism type I (OA1) is clinically characterized by impaired visual acuity, nystagmus, iris hypopigmentation with translucency, albinotic fundus, and macular hypoplasia together with normally pigmented skin and hair. However, it is easily misdiagnosed as congenital idiopathic nystagmus in some Chinese patients with OA1 caused by the G-protein coupled receptor 143 (GPR143) gene mutations. Mutations in the FERM domain-containing 7 (FRMD7) gene are responsible for the X-linked congenital idiopathic nystagmus. In this study, five Chinese families initially diagnosed as X-linked congenital nystagmus were recruited and patients underwent ophthalmological examinations. After direct sequencing of the FRMD7 and GPR143 genes, five mutations in GPR143 gene were detected in each of the five families, including a novel nonsense mutation of c.333G>A (p.W111X), two novel splicing mutations of c.360+1G>C and c.659-1G>A, a novel small deletion mutation of c.43_50dupGACGCAGC (p.L20PfsX25), and a previously reported missense mutation of c.703G>A (p.E235K). Optical coherence tomography (OCT) examination showed foveal hypoplasia in all the affected patients with nystagmus. Our study further expands the GPR143 mutation spectrum and contributes to the study of GPR143 molecular pathogenesis. Molecular diagnosis and optical coherence tomography (OCT) are two useful tools for differential diagnosis.

Purpose: Idiopathic congenital nystagmus (ICN) is a genetically heterogeneous disease. Thus far, the disease gene has been identified as the FERM domain containing 7 (FRMD7) gene. The purpose of this study was to elucidate the clinical and genetic characteristics of a four- generation Chinese family with ICN., Methods: The clinical data and the genomic DNA of a Chinese ICN family were collected following the provision of informed consent. All coding exons of the FRMD7 gene were amplified by PCR and then sequenced. Affinity GST-p21 activated kinase 2 (PAK2) precipitation was used to investigate whether this novel FRMD7 mutant influenced Rac1 signaling activation in the human embryonic kidney 293 T cells (HEK 293T) cells transiently cotransfected with wild-type or mutant FRMD7 and Rac1., Results: A novel missense mutation (c.635T>C) was identified in all affected members. Obligate female carriers were heterozygous in these mutations and the affected males were homozygous, consistent with X-linked inheritance. This mutation is a substitution of proline for leucine. Function analysis showed that this novel mutant influences Rac1 signaling in human HEK 293T cells., Conclusions: This study widens the mutation spectrum of the FRMD7 gene. This mutant was shown to activate GTPase Rac1 signaling in vitro; however, the quantity of activated Rac1 was obviously decreased compared with the wild type (p<0.05). Taken together, our data strongly support the hypothesis that the identified FRMD7 mutant influences GTPase Rac1 signaling, which regulates neurite development. This mutation may be related to the pathogenesis of X-linked ICN.

Congenital motor nystagmus (CMN) is characterized by early-onset bilateral ocular oscillations. To identify the disease locus for autosomal dominant CMN in a Chinese family 86001, clinical data, including slit lamp and funduscopic examination and blood samples were collected from family. Genomic DNA was prepared from leukocytes, and a genome-wide linkage scan was performed using 382 polymorphic microsatellite markers and two-point linkage analysis using the logarithm of odds (LOD) score method as implemented in the LINKAGE program package. Maximum two-point scores were calculated using ILINK, and LINKMAP was used for multipoint analysis. All nine affected individuals in the family showed typical phenotypes for CMN. Maximum two-point LOD scores (3.61 at θ=0) were obtained with D1S2619, D1S2877 and D1S2622.The 24.6 cM (28.07 Mb) linked region is flanked by markers D1S218 and D1S2655, placing the disease locus on chromosome 1q25.2-1q32.1. Multipoint analysis confirmed linkage to the region of D1S218 and D1S2655 with Maximum two-point scores of 3.61. The linkage interval overlaps with that of a newly reported CMN locus on 1q31-q32.2 and narrows down the linked region to 5.90 cM (5.92 Mb). This study confirms and refines a novel locus for autosomal dominant CMN to chromosome 1q31.3-q32.1 (5.90 cM) and demonstrates its presence in the Chinese population.

Purpose: To investigate the paired box 6 (PAX6) gene in two sporadic patients from southern China presenting with classic aniridia., Methods: The two sporadic patients underwent complete physical and ophthalmic examinations. Genomic DNA was extracted from the leukocytes of the peripheral blood collected from the families of the two sporadic patients and 100 unrelated control subjects from the same population. Exons 4-13 of PAX6 were amplified by polymerase chain reaction (PCR) and sequenced directly. The ophthalmic examinations included best-corrected visual acuity, slit-lamp examination, fundus examination, optical coherence tomography, and Pentacam and Goldmann perimetry., Results: The two patients were affected with aniridia accompanied by nystagmus. A heterozygous PAX6 frameshift mutation in exon 7, c.375&#95;376delAG (p.Arg125SerfsX7), was identified in sporadic patient 1 and not in any of the unaffected family members and normal controls. One novel mutation in exon 10, c.868&#95;871dupAGTT (p.Phe291X), was detected in sporadic patient 2. The frameshift mutation we identified has not previously been reported either in China or abroad., Conclusions: Although PAX6 mutations and polymorphisms have been reported in various ethnic groups, we report, for the first time, the identification of one new PAX6 mutation in Chinese aniridia patient.

Purpose: To identify a potential pathogenic mutation in a four-generation Chinese family with X-linked congenital nystagmus (XLCN)., Methods: Routine clinical examination and ophthalmic evaluation were performed on normal controls, two patients and two healthy members of the family. Genomic DNA was prepared from the peripheral blood of members of the family and from 50 normal controls. All coding exons and the intronic boundaries of the four-point-one (4.1), ezrin, radixin, moesin (FERM) domain-containing 7 (FRMD7) gene were amplified using polymerase chain reaction (PCR) followed by direct sequencing., Results: A previously unreported splicing mutation, c.163-1 G→T transversion (c.163-1 G>T), was detected preceding exon3 of FRMD7 in the patients but not in the unaffected family members and 50 unrelated healthy individuals., Conclusions: We identified a novel mutation (c.163-1 G→T) of FRMD7 in this Chinese family with XLCN. Our finding is the first report related to c.163-1 G→T mutation in FRMD7. The result expands the mutation spectrum of FRMD7 in association with congenital nystagmus.

Purpose: The purpose of the current research was to detect the underlying genetic defect in a Chinese family with X-linked congenital nystagmus and perform prenatal genetic diagnosis for their current pregnancy., Methods: A common clinical examination and an ophthalmic evaluation were performed on the proband, one carrier, and one unaffected member. Mutation analysis of the G protein-coupled receptor 143 (GPR143) and four-point-one (4.1), ezrin, radixin, moesin (FERM) domain-containing 7 (FRMD7) genes was performed by direct sequencing of PCR-amplified exons in the proband. The detected GPR143 mutation was tested in all available family members and 200 normal controls by direct sequencing., Results: Congenital nystagmus, obvious fundus hypopigmentation, and foveal hypoplasia were observed in the proband but not in the carriers or the unaffected members. A novel splicing mutation c.658+1 g>t not found in 200 unrelated controls was identified and co-segregated with X-linked ocular albinism (XLOA) in this family. The fetus (V:5) was hemizygous for this mutant allele., Conclusions: We identified a novel causative mutation of GPR143 in a five-generation Chinese family with XLOA. This expanded the mutation spectrum of GPR143 and provided data elucidating the diverse and variable effects of GPR143 mutations.

Purpose: To identify the gene mutations causing X-linked infantile nystagmus in two Chinese families (NYS003 and NYS008), of which the NYS003 family was assigned to the FERM domain-containing 7 (FRMD7) gene linked region in our previous study, and no mutations were found by direct sequencing., Methods: Two microsatellites, DXS1047 and DXS1001, were amplified using a PCR reaction for the linkage study in the NYS008 family. FRMD7 was sequenced and mutations were analyzed. Multiplex ligation-dependent probe amplification (MLPA) was used to detect FRMD7 mutations in the NYS003 family., Results: The NYS008 family yielded a maximum logarithm of odds (LOD) score of 1.91 at θ=0 with DXS1001. FRMD7 sequencing showed a nucleotide change of c. 623A>G in exon7 of the patients' FRMD7 gene, which was predicted to result in an H208R amino acid change. This novel mutation was absent in 100 normal Han Chinese controls. No FRMD7 gene mutations were detected by MLPA in the NYS003 family., Conclusions: We identified a novel mutation, c. 623A>G (p. H208R), in a Han Chinese family with infantile nystagmus. This mutation expands the mutation spectrum of FRMD7 and contributes to the research on the molecular pathogenesis of FRMD7.

Purpose: To screen mutations in the FERM domain-containing 7 (FRMD7) gene in a Chinese family with X-linked idiopathic congenital nystagmus (ICN)., Methods: It has been reported that FRMD7 mutations account for approximately 47% of X-linked nystagmus in Chinese patients. We collected 5 ml of blood samples from members of a family with X-linked ICN and 100 normal controls. Mutations in FRMD7 were determined by sequencing PCR products., Results: We identified a previously unreported 4 bp deletion in FRMD7 (c.1486-1489 del TTTT) in a Chinese family. The mutation co-segregated with the disease phenotype in patients and female carriers, while it was not detected in other relatives or in the 100 normal controls., Conclusions: Our results expand the spectrum of FRMD7 mutations causing ICN, and further confirm the role of FRMD7 in the pathogenesis of ICN. Direct sequencing of FRMD7 could be used as a diagnostic testing of idiopathic congenital nystagmus.

Purpose: Familial nystagmus complicated with cataract and iris anomalies are genetically heterogeneous, and the pathophysiological mechanisms remain unclear. It is anticipated that mutations in the paired box 6 (PAX6) gene play a major role in pathogenesis of malformations in anterior segment of the eye. In this study, we analyzed PAX6 in a Chinese pedigree of nystagmus, cataract and iris anomalies. This study will provide insights into the genetic basis of this disease., Methods: Complete ophthalmologic examinations were performed on four patients (excluding one dead patient) and four unaffected individuals in this four-generation family. All coding exons of PAX6 were amplified by polymerase chain reaction (PCR), sequenced and compared with reference database. The variations detected were evaluated in available family members as well as 110 normal controls. Possible changes in structure and function of the protein induced by amino acid variance were predicted by bioinformatics analysis., Results: Nystagmus, cataract or iris anomalies were found in all patients of this family, but the severity was different among these patients. A novel missense mutation in PAX6 was identified in all affected individuals but not in asymptomatic members and 110 normal controls. This mutation causes an amino acid substitution of proline to glutamine at position 118 (p.P118Q) of the paired domain of the PAX6 protein. Such a change may cause structural and functional changes of the protein based on bioinformatics analysis., Conclusions: This study added a novel mutation to the existing spectrum of PAX6 mutations, suggesting that a mutation in PAX6 correlated with anterior segment disorders observed in this family.

Purpose: To map and identify the genetic mutation underlying X-linked congenital nystagmus in a Chinese family., Methods: Genomic DNA was prepared from peripheral blood, and linkage analysis was performed using short tandem repeat (STR) polymorphism markers. We used Cyrillic software to manage pedigree and haplotype data and used MLINK to calculate LOD scores. Dye-terminator cycle-sequencing was used to detect the sequence variation of polymerase chain reaction (PCR)-amplified exons., Results: Linkage analysis mapped the disease-causing gene to Xp22.3 with a significant two-point LOD score (Z) at marker DXS7103 (Z=3.16, recombination fraction [theta]=0). Haplotype analysis in this region supported the result. In analyzing the candidate gene in the linked region, we found a 37-bp deletion in exon 1 of GPR143 in all male patients., Conclusions: The revealed 37-bp deletion in GPR143 is frameshift and is predicted to result in a truncated protein of 93 residues. These results indicate that this novel GPR143 mutation is associated with the congenital nystagmus observed in this Chinese family.

Purpose: Infantile nystagmus (IN) is an inherited disorder characterized by bilateral ocular oscillatory movements. Recently, mutations in FRMD7 were found to be responsible for X-linked idiopathic infantile nystagmus . We investigated the role of the FRMD7 gene mutations in seven Chinese families with infantile nystagmus., Methods: Linkage analysis was performed with fluorescently labeled microsatellite markers, DXS1001 and DXS1047. Analysis of FRMD7 gene mutations was performed by direct sequence to the whole coding regions and exon-intron boundaries of FRMD7 gene in all affected members in seven families with IN., Results: Five novel FRMD7 gene mutations, 70 G>T(p.G24W) in exon 2, c.689-690delAG (p.Ser232del) in exon8, c. 782G>A (p.R260Q) and c. 812G>T (p. C271F) in exon 9, and c. 910C>T (R303X) in exon 10, were identified in five of seven Chinese families with X-linked infantile nystagmus. But we didn't detect the FRMD7 gene mutation in one of seven families, although a positive LOD score of 2.42 (thetamax=0.1) was obtained at DXS1047 . We also found the same mutation, which is c. 782G>A (p.R260Q), occurred in two different families., Conclusions: This is first report that five kinds of FRMD7 gene mutation types occurred in Chinese families with IN, which further support that FRMD7 gene mutations are the underlying pathogenesis of the molecular mechanism for infantile nystagmus.

Objective: To study the mutation of FRMD7 gene in a Chinese family with congenital idiopathic nystagmus., Methods: Forty-six individuals in the Chinese family with congenital idiopathic nystagmus, including 16 patients, 19 normal siblings and 11 spouses, were investigated under informed consent. Genomic DNA of all 46 members was isolated by standard protocol. The X-linked inherited pattern was ascertained by investigating the history of the family members and the clinical feature of each individual. The genome scan on X chromosome was performed after PCR amplification for microsatellite markers. LOD scores were calculated with Linkage 5.1. Direct DNA sequence analysis was carried out to find the gene mutation responsible for the disease., Results: A maximum LOD score of 8.55 (theta=0) was obtained with polymorphic marker DXS1047. Haplotype construction of the family defined the disease interval between DXS8059 and DXS8033. Direct DNA sequence analysis revealed a heterozygous mutation of G990T in exon 9 of the FRMD7 gene in all patients, which was not present in unaffected family members., Conclusion: Congenital nystagmus is a clinically and genetically heterogeneous ocular movement disease. The mutation of G990T of the FRMD7 gene is the underlying molecular pathogenesis for this family with congenital nystagmus.

Purpose: Congenital motor nystagmus (CMN) is a relatively common oculomotor disorder characterized by bilateral uncontrollable ocular oscillations. Recently, the FRMD7 gene mutation has been identified as the genetic cause of CMN. The purpose of this study was to identify mutations of the FRMD7 gene in Chinese patients with CMN., Methods: Clinical data and genomic DNA of three Chinese CMN families were collected after informed consent. Genescan by two-point linkage analysis combined with haplotype analysis was performed and mutation screening of the FRMD7 gene was conducted by direct sequencing., Results: Maximum two-point LOD scores of 2.00, 1.76, and 1.16 at theta=0.00 were obtained with markers in proximity to the FRMD7 gene on chromosome Xp26 in the three CMN families. Mutation screening in the FRMD7 gene identified two novel missense mutations (c.781C>G and c.886G>C) and one reported nonsense mutation (c.1003C>T). These nucleotide alterations were not seen in unaffected members of the families or in 100 unrelated control subjects., Conclusions: This study widens the mutation spectrum of the FRMD7 gene.

Purpose: To identify mutations causing X-linked congenital motor nystagmus (XL-CMN) in Chinese families., Methods: Genomic DNA was prepared from peripheral blood leukocytes. Cycle sequencing was used to detect the sequence variation of the FERM domain containing 7 (FRMD7) gene, where mutations have been identified recently to associate with XL-CMN., Results: Sequencing of the coding and the adjacent intron regions of FRMD7 identified mutations in four families with XL-CMN, c.41-43delAGA (p.Lys14del) in exon 1, c.70G>A (p.Gly24Arg) in exon 2, c.436C>T (p.Arg146Trp) in exon 6, and c.685C>T (p.Arg229Cys) in exon 8, respectively, where the last two were novel. These mutations were not detected in 196 normal controls. In the two families with X-linked recessive CMN, females carrying a heterozygous mutation in FRMD7 did not have any sign of nystagmus., Conclusions: Our results provide additional evidence for mutations in FRMD7 as a common cause of XL-CMN and expand its mutation spectrum. CMN in a Chinese family with pure X-linked recessive pattern, previously mapped to Xq23-q27, is associated with the c.41-43delAGA mutation in FRMD7.