FRMD7 Research Articles

Truncated FRMD7 proteins in congenital Nystagmus: novel frameshift mutations and proteasomal pathway implications

Idiopathic congenital nystagmus (ICN) manifests as involuntary and periodic eye movements. To identify the genetic defect associated with X-linked ICN, Whole Exome Sequencing (WES) was conducted in two affected families. We identified two frameshift mutations in FRMD7, c.1492dupT/p.(Y498Lfs*15) and c.1616delG/p.(R539Kfs*2). Plasmids harboring the mutated genes and qPCR analysis revealed mRNA stability, evading degradation via the NMD pathway, and corroborated truncated protein production via Western-blot analysis. Notably, both truncated proteins were degraded through the proteasomal (ubiquitination) pathway, suggesting potential therapeutic avenues targeting this pathway for similar mutations. Moreover, we conducted a comprehensive analysis, summarizing 140 mutations within the FRMD7 gene. Our findings highlight the FERM and FA structural domains as mutation-prone regions. Interestingly, exons 9 and 12 are the most mutated regions, but 90% (28/31) mutations in exon 9 are missense while 84% (21/25) mutations in exon 12 are frameshift. A predominant occurrence of shift code mutations was observed in exons 11 and 12, possibly associated with the localization of premature termination codons (PTCs), leading to the generation of deleterious truncated proteins. Additionally, our conjecture suggests that the loss of FRMD7 protein function might not solely drive pathology; rather, the emergence of aberrant protein function could be pivotal in nystagmus etiology. We propose a dependence of FRMD7 protein normal function primarily on its anterior domain. Future investigations are warranted to validate this hypothesis.

Novel mutations of the X-linked genes associated with early-onset high myopia in five Chinese families

PurposeTo report novel pathogenic variants of X-linked genes in five Chinese families with early-onset high myopia (eoHM) by using whole-exome sequencing and analyzing the phenotypic features.Methods5 probands with X-linked recessive related eoHM were collected in Ningxia Eye Hospital from January 2021 to June 2022. The probands and their family members received comprehensive ophthalmic examinations,and DNA was abstracted from patients and family members. Whole-exome sequencing was performed on probands to screen the causative variants, and all suspected pathogenic variants were determined by Sanger sequencing and co-segregation analysis was performed on available family members. The pathogenicity of novel variants was predicted using silico analysis and evaluated according to ACMG guidelines. RT-qPCR was used to detect differences in the relative mRNAs expression of candidate gene in mRNAs available with the proband and family members in the pedigree 2. The relationship between genetic variants and clinical features was analyzed.ResultsAll probands were male, and all pedigrees conformed to an X-linked recessive inheritance pattern. They were diagnosed with high myopia at their first visits between 4 and 7 years old. Spherical equivalent ranged between − 6.00D and − 11.00D.The five novel hemizygous variants were found in the probands, containing frameshift deletion variant c.797_801del (p.Val266Alafs*75) of OPN1LW gene in the pedigree 1, nonsense variant c.513G > A (p.Trp171Ter)of RP2 gene in the pedigree 2, missense variant c.98G > T (p.Cys33Phe) of GPR143 gene in the pedigree 3, frameshift deletion variant c.1876_1877del (p.Met626Valfs*22) of FRMD7 gene in the pedigree 4 and inframe deletion variant c.670_ 675del (p.Glu192_ Glu193del) of HMGB3 gene in the pedigree 5. All variants were classified as pathogenic or likely pathogenic by the interpretation principles of HGMD sequence variants and ACMG guidelines. In family 2, RT-qPCR showed that the mRNA expression of RP2 gene was lower in the proband than in other normal family members, indicating that such variant caused an effect on gene function at the mRNA expression level. Further clinical examination showed that pedigrees 1, 2, 3, and 4 were diagnosed as X-linked recessive hereditary eye disease with early-onset high myopia, including quiescent cone dysfunction, retinitis pigmentosa, ocular albinism, and idiopathic congenital nystagmus respectively. The pedigree 5 had eoHM in the right eye and ptosis in both eyes.ConclusionIn this paper,we are the first to report five novel hemizygous variants in OPN1LW, RP2, GPR143, FRMD7, HMGB3 genes are associated with eoHM. Our study extends the genotypic spectrums for eoHM and better assists ophthalmologists in assessing, diagnosing, and conducting genetic screening for eoHM.

Nystagmus in Children - a Survey

Nystagmus describes an involuntary, periodic movement of one or both eyes. About 1/600 children and adolescents have nystagmus, most of them idiopathic infantile nystagmus (IIN), also called "congenital nystagmus", which can be caused by mutations in the FRMD7 gene. Other frequent forms of nystagmus are latent nystagmus, which is usually associated with infantile strabismus, and nystagmus associated with albinism. Sometimes difficult to distinguish in young infants is a sensory nystagmus, where a defect in the visual system reduces vision and causes nystagmus. Causes include retinal dystrophies, congenital stationary night blindness and structural ocular defects including optic nerve hypoplasia or dense bilateral congenital cataracts. Unilateral nystagmus can be the sign of an anterior visual pathway lesion. Seesaw nystagmus may be associated with suprasellar and mesodiencephalic lesions and - rarely - with retinal dystrophies.The ophthalmology plays a key role in identifying the form of nystagmus. Children with new onset nystagmus, with spasmus nutans, with vertical or unilateral nystagmus and those with seesaw nystagmus require neurologic evaluation including imaging of the brain.The treatment of nystagmus depends on the underlying cause. Even minor refractive errors should be corrected, contact lenses offer advantages over glasses.Gabapentin and memantine, possibly also carbonic anhydrase inhibitors, are effective in treating IIN, nystagmus in albinism and sensory nystagmus. Nevertheless, pharmacologic treatment of nystagmus is rarely used in children; the reasons are the limited effects on vision, the need for lifelong therapy, and potential side effects. Eye muscle surgery (Anderson procedure, Kestenbaum procedure) can correct a nystagmus-related anomalous head posture. The concept of "artifical divergence" of Cüppers may help to decrease nystagmus intensity in patients whose nystagmus dampens with convergence. The four-muscle-tenotomy, which involves disinsertion and reinsertion of the horizontal muscles at the original insertion of both eyes, has a proven but limited positive effect on visual acuity.

FRMD7 Gene Alterations in a Pakistani Family Associated with Congenital Idiopathic Nystagmus.

Congenital idiopathic nystagmus (CIN) is an oculomotor disorder characterized by repetitive and rapid involuntary movement of the eye that usually develops in the first six months after birth. Unlike other forms of nystagmus, CIN is widely associated with mutations in the FRMD7 gene. This study involves the molecular genetic analysis of a consanguineous Pakistani family with individuals suffering from CIN to undermine any potential pathogenic mutations. Blood samples were taken from affected and normal individuals of the family. Genomic DNA was extracted using an in-organic method. Whole Exome Sequencing (WES) and analysis were performed to find any mutations in the causative gene. To validate the existence and co-segregation of the FRMD7 gene variant found using WES, sanger sequencing was also carried out using primers that targeted all of the FRMD7 coding exons. Additionally, the pathogenicity of the identified variant was assessed using different bioinformatic tools. The WES results identified a novel nonsense mutation in the FRMD7 (c.443T>A; p. Leu148 *) gene in affected individuals from the Pakistani family, with CIN resulting in a premature termination codon, further resulting in the formation of a destabilized protein structure that was incomplete. Co-segregation analysis revealed that affected males are hemizygous for the mutated allele c.443T>A; p. Leu148 * and the affected mother is heterozygous. Overall, such molecular genetic studies expand our current knowledge of the mutations associated with the FRMD7 gene in Pakistani families with CIN and significantly enhance our understanding of the molecular mechanisms involved in genetic disorders.

Prospective study of pediatric patients presenting with idiopathic infantile nystagmus-Management and molecular diagnostics.

Idiopathic infantile nystagmus (IIN) is an inherited disorder occurring in the first 6 months of life, with no underlying retinal or neurological etiologies and is predominantly caused by mutations in the FRMD7 gene. IIN poses a diagnostic challenge as underlying pre-symptomatic “multisystem” disorders varying from benign to life-threatening should first be ruled out before nystagmus can be labeled as idiopathic. A multidisciplinary approach including multimodal ocular investigations and next-generation sequencing with whole-genome sequencing (WGS) or targeted gene panel testing is required to delineate the exact etiology. We report the clinical and genetic outcomes of 22 patients, from 22 unrelated families of diverse ethnicities, with IIN seen in the ocular genetics service at Moorfields Eye Hospital NHS Foundation Trust between 2016 and 2022. Thirty-six percent (8/22) received a confirmed molecular diagnosis with eight mutations identified in two genes (seven in FRMD7 including one novel variant c.706_707del; p. [Lys236Alafs*66], and one in GPR143). This study expands the mutational spectrum of IIN and highlights the significant role of an integrated care pathway and broader panel testing in excluding underlying pathologies.

Characterization of the Frmd7 Knock-Out Mice Generated by the EUCOMM/COMP Repository as a Model for Idiopathic Infantile Nystagmus (IIN).

In this study, we seek to exclude other pathophysiological mechanisms by which Frmd7 knock-down may cause Idiopathic Infantile Nystagmus (IIN) using the Frmd7.tm1a and Frmd7.tm1b murine models. We used a combination of genetic, histological and visual function techniques to characterize the role of Frmd7 gene in IIN using a novel murine model for the disease. We demonstrate that the Frmd7.tm1b allele represents a more robust model of Frmd7 knock-out at the mRNA level. The expression of Frmd7 was investigated using both antibody staining and X-gal staining confirming previous reports that Frmd7 expression in the retina is restricted to starburst amacrine cells and demonstrating that X-gal staining recapitulates the expression pattern in this model. Thus, it offers a useful tool for further expression studies. We also show that gross retinal morphology and electrophysiology are unchanged in these Frmd7 mutant models when compared with wild-type mice. High-speed eye-tracking recordings of Frmd7 mutant mice confirm a specific horizontal optokinetic reflex defect. In summary, our study confirms the likely role for Frmd7 in the optokinetic reflex in mice mediated by starburst amacrine cells. We show that the Frmd7.tm1b model provides a more robust knock-out than the Frmd7.tm1a model at the mRNA level, although the functional consequence is unchanged. Finally, we establish a robust eye-tracking technique in mice that can be used in a variety of future studies using this model and others. Although our data highlight a deficit in the optiokinetic reflex as a result of the starburst amacrine cells in the retina, this does not rule out the involvement of other cells, in the brain or the retina where Frmd7 is expressed, in the pathophysiology of IIN.

Nystagmus-related FRMD7 gene influences the maturation and complexities of neuronal processes in human neurons.

AimsIdiopathic congenital nystagmus (ICN) is an oculomotor disorder caused by the defects in the ocular motor control regions of the brain. Mutations in FRMD7, a member of the FERM family of proteins, associated with cytoskeletal dynamics, are the most frequent causes of X‐linked ICN. Previous studies illustrated that FRMD7 is involved in the elongation of neurites during neuronal development; however, almost all the studies were performed on mice cell models. The complexity in the human neuronal network might suggest a unique vulnerability of human neurons to FRMD7 mutations.MethodsHerein, we successfully established human neuronal cell models with FRMD7 mutations, from fibroblasts‐reprogrammed neurons (iNs). In these neurons, the complexity of the neuronal processes was measured by the induced ratio, total neurite length, the number of terminals, and the number of maturation neurons.ResultsThe complexity of the neuronal processes was greatly reduced during various reprogramming stages in the presence of FRMD7 mutations. Consistently, the expression of the three main Rho GTPases was significantly increased by FRMD7 mutations. Interestingly, a slightly diverse phenotype is observed in different derived neurons.ConclusionWe established ideal human neuron models and confirmed that the mutation in FRMD7 influences the maturation and complexities of neuronal processes, which might be involved with the Rho GTPase signaling.

Mutations analysis of FRMD7 gene in idiopathic congenital nystagmus families

Objective To reveal the pathogenic mutations in Chinese families with idiopathic congenital nystagmus(ICN) Methods Six families with ICN were recruited from Subei People's Hospital.DNA was extracted from peripheral blood samples of all participants.All coding and exon-intronic boundary regions of the targeted gene FRMD7 were amplified with PCR and sequenced using Sanger sequencing to detect potential pathogenic mutations.This study followed the Helsinki Declaration and was approved by the Ethics Committee of Subei People's Hospital (NO.2015KY-126). All patients or their guardians signed informed consent. Results Three mutations (c.902A>G, c.1944T>A and 1945G>T) were screened in two families after co-segregation validation of intrafamilial genotype-phenotype, c.1944T>A and 1945G>T were newly detected mutations which were not detected in 100 normal controls.No significant mutations were found in the FRMD7 coding region and adjacent splicing sites in the probands of the other four families. Conclusions Two novel pathogenic mutations of FRMD7 are discovered, which expands the pathogenic mutational spectrum of FRMD7 gene causing ICN. Key words: Idiopathic congenital nystagmus; FRMD7 gene; Missense mutation; Nonsense mutation

Nystagmus: A FRMD7 Prospective

Nystagmus is involuntary up and down, to and fro and oscillatory movement of eye. Nystagmus is caused by different inheritance pattern, which can be; AD (autosomal dominant), AR (autosomal recessive) and X-linked. This review elaborates the mutational canvas of FRMD7 gene involved in X-linked Nystagmus. In Pakistan the publication is either not available or no research findings has been reported for FRMD7 gene according to our knowledge.

X-linked inheritances recessive of congenital nystagmus and autosomal dominant inheritances of congenital cataracts coexist in a Chinese family: a case report and literature review

BackgroundCongenital nystagmus (CN) and congenital cataracts are distinct eye diseases and are usually isolated. Cases with CN and congenital cataracts caused by different genes in one family have been rarely reported.Case presentationA 27-year-old man presented with CN and congenital cataracts and he underwent cataract extraction 2 weeks after birth. Three years later, he had posterior chamber intraocular lens implantation. The proband’s mother was only afflicted by bilateral lens opacities. Lensectomy was performed in both eyes at age 15. The proband’s daughter had bilateral central cataracts and no nystagmus. She had undergone cataract extraction when she was two months old. In this family, 8 affected individuals were affected by bilateral cataracts, and three of them presented with CN. The genetic analysis was performed using a specific Hereditary Ophthalmological Disease Gene Panel on proband and his parents (one of which was a patient). PCR and Sanger sequencing verified the presence of these variants in all members of the family. The novel mutation, c.498-3C > T, in FRMD7 explains why X-Linked recessive inheritance of CN was found in a subset of patients. A heterozygous mutation of the GJA8 gene (c.139G > C), was identified in all patients and thus explains the autosomal dominant pattern of inheritance of congenital cataracts within the family.ConclusionsThis is the first time that FRMD7 and GJA8 gene mutations have been linked to the pathogenesis of a family with both CN and congenital cataracts. The phenomenon of two different genetic patterns coexisting in one family is rare.

Identification of a novel idiopathic congenital nystagmus‑causing missense mutation, p.G296C, in the FRMD7 gene.

Exploring the genetic basis for idiopathic congenital nystagmus is critical for improving our understanding of its molecular pathogenesis. In the present study, direct sequencing using gene specific primers was performed in order to identify the causative mutations in two brothers from a Chinese family who had been diagnosed with idiopathic congenital nystagmus. A comprehensive ophthalmological examination, including eye movement recordings, fundus examination, and retinal optical coherence tomography imaging was also conducted, to characterize the disease phenotype. The results revealed that the two brothers exhibited clear signs of nystagmus without any other ocular anomalies. Direct sequencing revealed a G to T transition (c.886G>T) in exon 9 of the four-point-one, ezrin, radixin, moesin domain-containing 7 (FRMD7) gene, which resulted in a conservative substitution of glycine to cysteine at codon 296 (p.G296C), leading to idiopathic congenital nystagmus in the two affected brothers. c.886G>T is a novel idiopathic congenital nystagmus-inducing mutation in the FRMD7 gene. This finding expands the spectrum of known gene mutations in idiopathic congenital nystagmus, and may be useful for faster gene diagnosis, prenatal testing, the development of potential gene therapies, and for improving the understanding of the molecular pathogenesis of idiopathic congenital nystagmus.

Clinical feature and waveform in infantile nystagmus syndrome in children with FRMD7 gene mutations.

Infant nystagmus sydrome presents as involuntary eye movement disorder and can affect seriously ocular function. We performed a retrospective study of clinical data and FRMD7 genetic test results in 12 cases of infantile nystagmus syndrome to correlate waveform, stereopsis, and visual acuity. The patients (age 6.40±2.67 years) had FRMD7 mutations as follows: missense in eight cases, shear in two cases, frameshift in one case, and non-frameshift in one case. Horizontal jerk waveform was observed in six cases, versus horizontal pendulum in five cases and dual jerk in one case. The uncorrected visual acuity (24 eyes) was 0.21±0.12, compared with a corrected visual acuity (24 eyes) of 0.32±0.14. All patients had simultaneous perception, versus fusion function in 10 cases (83.33%) and stereoscopic vision in seven cases (58.33%) using the synoptophore. Eleven cases (91.67%) detected the stereo fly, compared with five cases (41.67%) for stereoscopic circles and seven cases (58.33%) for stereoscopic animals by Titmus test. Stereoscopic vision using the synoptophore did not correlate with the frequency, amplitude, or intensity of nystagmus or with corrected binocular visual acuity. The infantile nystagmus syndrome with FRMD7 mutations in our cases was caused primarily de novo and missense mutations. Visual acuity and binocular visual function were significant impaired, and the waveform was generally horizontal jerk. Also, an infrared videonystagmogram can record the frequency, amplitude, and intensity of nystagmus accurately.

X-Linked Idiopathic Infantile Nystagmus (XLIIN): Case Report and Review of Literature

Infantile nystagmus syndrome (INS) is one of the most common forms of nystagmus. It can occur in isolation or with other ocular anomalies. While nystagmus is usually sporadic, familial cases exist and are most commonly X-linked with incomplete penetrance and variable expressivity. There are over 45 mutations reported in the FRMD7 gene. This review describes the possible underlying mechanisms of infantile nystagmus syndrome, clinical characterization, and principles of management including behavioral, refractive, pharmacological, and surgical options as well as determines the genetic basis of INS in one large Caucasian family with a novel mutation in FRMD7. Newer generation optical coherence tomography (OCT) allows for accurate phenotypical characterization of genetic subtypes of INS. Further studies into identifying unknown genetic mutations involved in infantile nystagmus syndrome will allow for development of cellular and animal models to help classify INS and guide future therapies.

Molecular genetic analysis of patients with sporadic and X-linked infantile nystagmus

ObjectivesInfantile 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...

Diagnosis, assessment and management of nystagmus in childhood

Abstract Nystagmus is a rhythmical, repetitive and involuntary movement of the eyes. It is usually from side to side, but sometimes up and down or in a circular motion. It can be distressing to the child and their carers and leads to reduced visual acuity due to the excessive motion of images on the retina. It is helpful to distinguish between infantile nystagmus and acquired nystagmus. Infantile nystagmus usually appears by 3–6 months. Infantile nystagmus can occur with poor vision, or visual deprivation in early life due to congenital cataracts, optic nerve hypoplasia, retinal dystrophies or disease, can be associated to albinism or it can be part of a neurological syndromes or diseases. Neurological disease should be suspected when the nystagmus is asymmetrical or unilateral. Infantile nystagmus can be hereditary, the most common and best analysed form being a mutation of the FRMD7 gene on chromosome Xq26.2. Novel methods to record eye movements and recent advances in the field of genetics have contributed to the improvement in diagnosis and management of nystagmus in children. Glasses, contact lenses and prisms help in improving vision. Pharmacological treatment exists to reduce nystagmus; however, as there are very few randomized controlled trials in this area, most pharmacological treatment options in nystagmus remain empirical. Eye muscle surgery may help in children with abnormal head posture to correct the defect and alleviate neck problems that can arise due to an abnormal head posture.

A start codon mutation of the FRMD7 gene in two Korean families with idiopathic infantile nystagmus.

Idiopathic infantile nystagmus (IIN) is the involuntary oscillation of the eyes with onset in the first few months of life. The most common form of inheritance is X-linked, and mutations in FRMD7 gene are a major cause. To identify the FRMD7 gene mutations associated with X-linked IIN, we performed PCR-based DNA direct sequencing in 4 affected subjects from 2 Korean families. We also assessed structural abnormalities of retina and optic nerve head using optical coherence tomography (OCT). Genetic analysis revealed a A>G transversion at nucleotide c.1, the first base of the start codon. This mutation leads to the loss of the primary start codon ATG for methionine, which is replaced by a triplet GTG for valine. The alternative in-frame start codon is not present around a mutation. OCT revealed the morphological changes within the optic nerve head, including shallow cup depth and small cup-to-disc ratio. In summary, we identified a novel start codon mutation within the FRMD7 gene of 2 Korean families. Our data expands the mutation spectrum of FRMD7 causing IIN. We also demonstrated abnormal developments of afferent system in patients with FRMD7 mutations using OCT, which may help to understand the etiological factor in development of nystagmus.

Heterogeneous phenotype in a family with the FERM domain-containing 7 gene R335X mutation

ObjectiveInfantile nystagmus (IN) is characterized by bilateral involuntary, periodic, and predominantly ocular oscillations. In this article, we describe a mutation screen conducted on a 4-generation family in which 4 patients were affected with X-linked IN (XLIN). DesignExperimental study. ParticipantsA 4-generation Chinese Han family including 4 symptomatic members with IN and 200 normal male controls. MethodsDNA was extracted from peripheral blood, and the FERM domain-containing 7 gene (FRMD7) was amplified on DNA samples of all the available family members. The mutation screen was conducted by performing direct DNA sequencing. ResultsA nonsense mutation (R335X) in the FRMD7 gene was identified in 4 male patients and an asymptomatic female member. ConclusionsAlthough the R335X mutation in the FRMD7 gene has been previously described, the clinical features, including both disease penetrance and severity, among individuals with FRMD7 mutation in our family vary greatly. One female member with the heterozygous R335X mutation had no clinical manifestation of the disease. This incomplete penetrance suggests that random X-chromosome inactivation may play a role in the pathogenesis of IN, and that loss of functional FRMD7 may account for the development of this disorder. Our findings may be helpful in the genetic counseling of patients with nystagmus.

Aetiology of infantile nystagmus

Mechanisms underlying infantile nystagmus are unclear. The aim of this review is to outline recent developments in understanding the aetiology of infantile nystagmus. There have been advances in understanding mechanisms underlying idiopathic infantile nystagmus, which has progressed through determining the role of the FRMD7 gene in controlling neurite outgrowth, and albinism, in which recent models have investigated the possibility of retinal miswiring leading to nystagmus. We also briefly review aetiology of infantile nystagmus in afferent visual deficits caused by ocular disease, and PAX6 mutations. Improved phenotypical characterization of all these infantile nystagmus subtypes has been achieved recently through high-resolution retinal imaging using optical coherence tomography. Several new hypotheses proposing common mechanisms that could underlie various infantile nystagmus subtypes are also highlighted. Although there is still no consensus of opinion regarding the mechanisms causing infantile nystagmus, identification of new genes and determining their cellular function, phenotypical characterization of genetic subtypes, and improvements in animal models have significantly advanced our understanding of infantile nystagmus. These recent developments pave the way to achieving a much clearer picture of infantile nystagmus aetiology in the future.

Identification of Three Novel Mutations in the FRMD7 Gene for X-linked Idiopathic Congenital Nystagmus

Idiopathic congenital nystagmus (ICN) consists of involuntary and periodic ocular motility, often with seriously reduced visual acuity. To identify the genetic defects associated with X-linked ICN, we performed PCR-based DNA direct sequencing of two candidate genes, FRMD7 and GPR143, in four families. Mutation analysis led to identification of three novel mutations, p.S260R, p.Q487X, and p.V549Y fsX554, in FRMD7 in three of the recruited families. Results from structural modeling indicated that the p.S260R may potentially disrupt FRMD7 function through loss of a phosphorylation site and/or interference with protein-protein interactions. Both p.Q487X, and p.V549Y fsX554 mutations were predicted to generate nonfunctional truncated proteins. Using a capture next generation sequencing method, we excluded CASK as the responsible gene for the remaining family. Combining sequence analysis and structural modeling, we report three novel mutations in FRMD7 in three independent families with XLICN, and provide molecular insights for future XLICN diagnosis and treatment.

Identifcation of a Novel Mutation p.I240T in the FRMD7 gene in a Family with Congenital Nystagmus

Congenital Nystagmus (CN) is a genetically heterogeneous ocular disease, which causes a significant proportion of childhood visual impairment. To identify the underlying genetic defect of a CN family, twenty-two members were recruited. Genotype analysis showed that affected individuals shared a common haplotype with markers flanking FRMD7 locus. Sequencing FRMD7 revealed a T > C transition in exon 8, causing a conservative substitution of Isoleucine to Tyrosine at codon 240. By protein structural modeling, we found the mutation may disrupt the hydrophobic core and destabilize the protein structure. We reviewed the literature and found that exons 2, 8, and 9 (11.4% of the sequence of FRMD7 mRNA) represent the majority (55.3%) of the reported FRMD7 mutations. In summary, we identified a novel mutation in FRMD7, showed its molecular consequence, and revealed the mutation-rich exons of the FRMD7 gene. Collectively, this provides molecular insights for future CN clinical genetic diagnosis and treatment.