Frequent Causative Gene Research Articles

Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes.

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing-a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.

Genetic research of inherited peripheral neuropathies

AbstractBackgroundOur department has been conducting genetic research on hereditary neuropathies, with a focus on the Charcot–Marie–Tooth (CMT) disease and other inherited peripheral neuropathies for the past 20 years. The CMT disease is an untreatable disease characterized by progressive muscle weakness, atrophy, and sensory impairment, primarily affecting the peripheral nerves.Materials and MethodsIn our institution, we collected blood samples from patients with the CMT disease, nationwide, and performed comprehensive genetic testing to elucidate its underlying causes.ResultUsing next‐generation sequencing (NGS), we successfully discovered two novel causative genes of the CMT disease, membrane metalloendopeptidase (MME), and cytochrome c oxidase assembly factor 7, via whole exome analysis of previously unidentified cases. These findings, combined with the comprehensive analysis enabled by NGS, have significantly improved the diagnostic rate of this disease.ConclusionNotably, the MME gene has been reported as the most frequent causative gene for autosomal recessive CMT disease, attracting global attention and subsequent research efforts. Accurate genetic diagnosis for each patient serves as a crucial first step toward understanding hereditary diseases. The identification of new causes of the CMT disease can assist in elucidating the molecular mechanisms involved completely, further contributing to the development of effective treatment approaches, including gene therapies.

Clinico-pathological and gene features of 15 nemaline myopathy patients from a single Chinese neuromuscular center.

Nemaline myopathy, the most common of the congenital myopathies, is caused by various genetic mutations. In this study, we attempted to investigate the clinical features, muscle pathology and genetic features of 15 patients with nemaline myopathy. Among the 15 patients, there were 9 (60.00%) males and 6 (40.00%) females, and 9 (60.00%) of them came from three families respectively. The age of seeing a doctor ranged from 9 to 52years old, the age of onset was from 5 to 23years old, and the duration of disease ranged from 3 to 35years. Ten out of the 15 patients had high arched palate and elongated face. Only one patient had mild respiratory muscle involvement and none had dysphagia. Muscle biopsies were performed in 9 out of the 15 patients. Pathologically, muscle fibers of different sizes, atrophic muscle fibers and compensatory hypertrophic fibers could be found, and occasionally degenerated and necrotic muscle fibers were observed. Different degrees of nemaline bodies aggregation could be seen in all 9 patients. The distribution of type I and type II muscle fibers were significantly abnormal in patients with nemaline myopathy caused by NEB gene, however, it was basically normal in patients with nemaline myopathy caused by TPM3 gene and ACTA1 gene. Electron microscopic analysis of 6 patients showed that nemaline bodies aggregated between myofibrils were found in 5(83.33%) cases, and most of them were located near the Z band, but no intranuclear rods were found. The gene analysis of 15 NM patients showed that three NM-related genes were harbored, including 11 (73.33%) patients with NEB, 3 (20.00%) patients with TPM3, and 1 (6.67%) patient with ACTA1, respectively. A total of 12 mutation sites were identified and included 10 (83.33%) mutations in exon and 2(16.67%) mutations in intron. The clinical phenotype of nemaline myopathy is highly heterogeneous. Muscle pathology shows that nemaline bodies aggregation is an important feature for the diagnosis of NM. NEB is the most frequent causative gene in this cohort. The splicing mutation, c.21522 + 3A > G may be the hotspot mutation of the NEB gene in Chinese NM patients.

Identification of Genomic Alterations in Thai Patients With Colorectal Cancer Using Next-Generation Sequencing-Based Multigene Cancer Panel.

Introduction Colorectal cancer (CRC) is one of the leading causes of death and illness in the general population. Although the incidence of CRC is steadily decreasing worldwide, it is being diagnosed more in individuals under 50 years of age. Multiple disease-causing variants have been reported to be involved in the development of CRC. This study aimed to investigate the molecular and clinical characteristics of Thai patients with CRC. Methods NGS-based multigene cancer panel testing was performed on 21 unrelated patients. Target enrichment was performed using a custom-designed Ion AmpliSeq on-demand panel. Thirty-six genes associated with CRC and other cancer were analyzed for variant detection. Results Sixteen variants (five nonsense, eight missense, two deletions, and one duplication) in nine genes were identified in 12 patients. Eight (66.7%) patients harboring disease-causing deleterious variants in genes APC, ATM, BRCA2, MSH2, and MUTYH. One of the eight patients also carried additional heterozygous variants in genes ATM, BMPR1A, and MUTYH. In addition, four patients carried variants of uncertain significance in genes APC, MLH1, MSH2, STK11, and TP53. Among all detected genes, APC was the most frequent causative gene observed in CRC patients, which is consistent with previous reports. Conclusion This study demonstrated the comprehensive molecular and clinical characterization of CRC patients. These findings showed the benefits of using multigene cancer panel sequencing for pathogenic gene detection and showed the prevalence of genetic aberrations in Thai patients with CRC.

Coffin-Siris syndrome and cancer susceptibility

Coffin-Siris syndrome (CSS) is a rare neurodevelopmental disorder that is associated with multiple congenital anomalies and caused by de novo monoallelic germline pathogenic variants in BAF-complex genes. Despite their function as tumor suppressors, the cancer risk in patients with CSS remains unclear. We analyzed cancer sequencing data sets, conducted a comprehensive literature review of patients with CSS diagnosed with malignancies, and examined a cohort of 376 CSS registry patients to estimate cancer frequency. A review of the literature identified several reports of patients with CSS diagnosed with a malignancy, with ARID1A being the most frequent causative gene and associated with hepatoblastoma in 3 cases. Although no cases of malignancy were reported among the patients in the CSS registry, only 26 patients with ARID1A-CSS were available for analysis. Combining these patients with all cases reported in the literature led to the estimate of hepatoblastoma prevalence in ARID1A-CSS of 3.6% (95% CI 0.79%-10.4%). Our findings suggest the hepatoblastoma risk among patients with ARID1A-CSS may exceed the established 1% risk threshold and therefore warrant surveillance. There remains insufficient evidence to support any other CSS gene-cancer association, emphasizing the need for further systematic study.

New insights into CC2D2A-related Joubert syndrome

PurposeIn this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes,...

Genetic Profile of Patients with Limb-Girdle Muscle Weakness in the Chilean Population.

Hereditary myopathies are a group of genetically determined muscle disorders comprising more than 300 entities. In Chile, there are no specific registries of the distinct forms of these myopathies. We now report the genetic findings of a series of Chilean patients presenting with limb-girdle muscle weakness of unknown etiology. Eighty-two patients were explored using high-throughput sequencing approaches with neuromuscular gene panels, establishing a definite genetic diagnosis in 49 patients (59.8%) and a highly probable genetic diagnosis in eight additional cases (9.8%). The most frequent causative genes identified were DYSF and CAPN3, accounting for 22% and 8.5% of the cases, respectively, followed by DMD (4.9%) and RYR1 (4.9%). The remaining 17 causative genes were present in one or two cases only. Twelve novel variants were identified. Five patients (6.1%) carried a variant of uncertain significance in genes partially matching the clinical phenotype. Twenty patients (24.4%) did not carry a pathogenic or likely pathogenic variant in the phenotypically related genes, including five patients (6.1%) presenting an autoimmune neuromuscular disorder. The relative frequency of the different forms of myopathy in Chile is like that of other series reported from different regions of the world with perhaps a relatively higher incidence of dysferlinopathy.

The Phenotype and Genotype of Congenital Myopathies Based on a Large Pediatric Cohort

BackgroundCongenital myopathies (CMs) are a clinically and genetically heterogeneous group of hereditary muscular disorders. The distribution of genetic and histologic subtypes has been addressed in only a few cohorts, and the relationship between phenotypes and genotypes is only partially understood. MethodsThis is a retrospective cross-sectional data collection study conducted at a single center. The clinical, histopathological, and molecular characterization of 104 patients with CM is reported. ResultsThe most common histopathological subtype was core myopathy (42%). Patients with severe endomysial fibrosis were more commonly unable to walk than patients with only a mild-grade endomysial fibrosis (56% vs 16%). Inability to walk was also more prevalent in patients with severe fatty replacement (44% vs 19%). The genetic etiology was more frequently identified among those patients with “specific” histologic findings (74% vs 62%). A definite molecular diagnosis was reached in 65 of 104 patients (62%), with RYR1 (24/104) and TTN (8/104) being the most frequent causative genes. Neonatal onset occurred in 56%. Independent ambulation was achieved by 74%. Patients who walked late were more likely to become wheelchair-dependent. Respiratory support was needed in one of three patients. Gastrostomy placement was required in 15%. Cardiac involvement was observed in 3%, scoliosis in 43%, and intellectual disability in 6%. ConclusionsThis study provides an updated picture of the clinical, histopathological, and molecular landscape of CMs. Independently of the causative gene, fibrosis and fatty replacement in muscle biopsy specimens are associated with clinical severity. Mutations in TTN are responsible for a higher proportion of cases than previously thought.

Mutational and clinical spectrum in a cohort of Chinese patients with hereditary nemaline myopathy.

Hereditary nemaline myopathy (NM) is one of the most common congenital myopathies with the histopathological findings of nemaline bodies. We used targeted next-generation sequencing to identify causative mutations in 48 NM patients with confirmed myopathological diagnosis, analyze the mutational spectrum and phenotypic features. Furthermore, reverse transcription polymerase chain reaction (RT-PCR) was used to confirm the pathogenic effect of one nebulin (NEB) splicing variant. The results showed that variants were found in five NM-associated genes, including NEB, actin alpha 1 (ACTA1), troponin T1, Kelch repeat and BTB domain-containing 13, and cofilin-2, in 34 (73.9%), 7 (15.2%), 3 (6.5%), 1 (2.2%), and 1 (2.2%) patients, respectively, in a total of 46/48 (95.8%) NM patients. Of the total 64 variants identified, 51 were novel variants including 26 pathogenic, 1 probably pathogenic, and 24 variant of uncertain significance (VUS). Notably, one NEB splicing mutation, c.21417+3A>G causing exon 144 splicing (NM_001164508.1), as confirmed by RT-PCR, was found in 52.9% (18 patients) of NEB variant-carrying patients. Typical congenital NM, the most common clinical subtype (60.4%), was associated with five NM genes. We concluded that hereditary NM showed a highly variable genetic spectrum. NEB was the most frequent causative gene in this Chinese cohort, followed by ACTA1. We found a hotspot splicing mutation in NEB among Chinese cohort.

Familial Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is the most rapidly progressive motor neuron disease (MND) in adults, characterized by the selective death of motor neurons in the motor cortex, brainstem, and spinal cord. Riluzole and edaravone are the only approved drugs available in Japan to date. Approximately 10% of ALS cases are familial in rature, defined as the existence of disease-causing mutation. SOD1 is the most frequent causative gene for ALS among Japanese individuals, while C9orf72 mutation is more prevalent in Western countries. Genotype-phenotype correlation described in the literature of familial ALS enables to establish models of the disease. This review article describes the clinical characteristics of familial ALS based on each disease-causing mutation. The pathomechanism of ALS including proteostasis, RNA metabolism, and axonal pathology are discussed in detail. We also reviewed the status of development of therapeutic strategies for familial ALS based on analysis of animal models and induced pluripotent stem cells.

C9orf72 Protein Plasmatic Concentrations Are Similar between C9ORF72 Expansion Carriers and Noncarriers in Frontotemporal Dementia

Background/Aims: The aim of the study was to assess the theory of haploinsufficiency in C9ORF72 expansion carriers, the most frequent causative gene of frontotemporal dementia. Methods: Plasmatic concentrations of C9orf72 protein were measured in 33 patients suspected of familial frontotemporal dementia using an enzyme-linked immunosorbent assay. Results: No difference was observed between C9ORF72 expansion carriers (21.2% of patients) and noncarriers (78.8% of patients). C9orf72 protein determination is not a suitable biomarker for screening C9ORF72 expansion carriers. Conclusion: Our results provide new evidence against the hypothesis of haploinsufficiency leading to frontotemporal dementia in C9ORF72 expansion carriers.

CONGENITAL MYOPATHIES: NEMALINE AND TITINOPATHIES: P.231The clinical, genetic, and pathological findings in a Chinese cohort of patients with hereditary nemaline myopathy

We aimed to identify the causative mutations of hereditary nemaline myopathy and to investigate the clinical, and pathological features in various genotypes. Methods: We recruited 48 patients with hereditary nemaline myopathy who had been diagnosed by muscle biopsies in our neuromuscular pathology lab from 2007 to 2017. Their clinical data and myopathological findings were retrospectively collected and analyzed. Next generation sequencing was used to identify the causative gene mutations in 40 patients. The onset age of these 48 patients ranged from 0 to 60 years old and the disease course ranged from 2 months to 38 years. Clinically, 23, 14 and 11 patients were typical congenital type, childhood or juvenile onset type and adult onset type, respectively. Molecular genetic analysis in 40 patients revealed possible pathogenic variants in 32 patients (80.00%), including 8 known mutation and 42 novel variants. NEB gene was the most frequent (23 patients, 57.50%), followed by ACTA1 (4 patients, 10.00%), RYR1 (2 patients, 5.00%), KBTBD13 genes (1 patient, 2.50%), TNNT1 (1 patient, 2.50%), and MYO18B (1 patient, 2.50%). Pathologically, thirteen patients showed coexistence of other myopathological features in addition to the presence of nemaline bodies in the muscle fibers, i.e., minicores in 4, cores in 3, central nuclei in 3 and fiber type disproportion in 3 patients. Nemaline bodies were present subsarcolemmally or in the cytoplasm of muscle fibers in patients with NEB mutation. In patients with ACTA1 mutation, nemaline bodies appeared in cluster or as thin filament in the region of disrupted myofibril. In patients with RYR1 mutation, there were rod-like structures formed by distorted Z-discs in the region of disrupted myofibrils. Hereditary nemaline myopathy showed wide clinical and genetic spectrum. Myopathological changes also revealed some difference depending on different genotypes. NEB is the most frequent causative gene in our patient cohort.

Genetic diagnosis of steroid-resistant nephrotic syndrome in a longitudinal collection of Czech and Slovak patients: a high proportion of causative variants in NUP93.

Steroid-resistant nephrotic syndrome (SRNS) has a heterogeneous spectrum of monogenic causes that substantially differ among populations. The aim of this study was to analyse the genetic aetiology of SRNS in Czech and Slovak paediatric patients. We analysed clinical data from 74 patients (38 boys) with congenital (15%), infant (14%), and childhood-onset (71%) SRNS collected from the Czech Republic and Slovakia from 2000 to 2017 (inclusive). The DNA samples were first analysed by Sanger sequencing (genes NPHS2, NPHS1, and WT1) and then by next generation sequencing (NGS) using a targeted panel of 48 genes previously associated with SRNS. Family segregation of the causative variants was confirmed by Sanger sequencing when possible. Genetic diagnosis was established in 28/74 patients (38%) based on findings of pathogenic or likely pathogenic causative variants in genotypes conforming to the expected mode of inheritance. Sanger sequencing diagnosed 26% of patients, whereas second-tier testing by a targeted NGS panel diagnosed a further 12%. Frequent causative genes were NPHS2 (15%), WT1 (9.5%), and surprisingly NUP93 with four (5.4%) unrelated cases. Additional causative genes included COQ2 (two patients), NPHS1, INF2, DGKE, and LMX1B (one patient each). Compared with outright use of NGS, our tiered genetic testing strategy was considerably more rapid and marginally less expensive. Apart from a high aetiological fraction of NPHS2 and WT1 genes, our study has identified an unexpectedly high frequency of a limited set of presumably ancestral causative mutations in NUP93. The results may aid in tailoring testing strategies in Central European populations.

Clinical and genetic diversities of Charcot‐Marie‐Tooth disease with MFN2 mutations in a large case study

Charcot‐Marie‐Tooth disease (CMT) constitutes a heterogeneous group affecting motor and sensory neurons in the peripheral nervous system. MFN2 mutations are the most common cause of axonal CMT. We describe the clinical and mutational spectra of CMT patients harboring MFN2 mutations in Japan. We analyzed 1,334 unrelated patients with clinically suspected CMT referred by neurological and neuropediatric departments throughout Japan. We conducted mutation screening using a DNA microarray, targeted resequencing, and whole‐exome sequencing. We identified pathogenic or likely pathogenic MFN2 variants from 79 CMT patients, comprising 44 heterozygous and 1 compound heterozygous variants. A total of 15 novel variants were detected. An autosomal dominant family history was determined in 43 cases, and the remaining 36 cases were reported as sporadic with no family history. The mean onset age of CMT in these patients was 12 ± 14 (range 0–59) years. We observed neuropathic symptoms in all patients. Some had optic atrophy, vocal cord paralysis, or spasticity. We detected a compound heterozygous MFN2 mutation in a patient with a severe phenotype and the co‐occurrence of MFN2 and PMP22 mutations in a patient with an uncommon phenotype. MFN2 is the most frequent causative gene of CMT2 in Japan. We present 15 novel variants and broad clinical and mutational spectra of Japanese MFN2‐related CMT patients. Regardless of the onset age and inheritance pattern, MFN2 gene analysis should be performed. Combinations of causative genes should be considered to explain the phenotypic diversity.

P.185 - Pathologically and genetically diagnosed familial amyloid polyneuropathy

Familial amyloid polyneuropathy (FAP) is an autosomal dominantly inherited disorder, in which transthyretin (TTR) is the most frequent causative gene. TTR-related FAP has been mainly reported in Portugal, Japan, Sweden, and only a few families have been diagnosed in Korea so far. Herein, we report another family with FAP in Korea. A 47-year-old man presented with 3-year history of numbness in distal extremities and orthostatic dizziness. Progressive leg weakness developed 2 years prior to the visit, which was followed by constipation, dry mouth, and dry eyes. His mother had been diagnosed as cardiac amyloidosis and died in her 60s. On examination, muscle atrophy and weakness were evident in both legs, accompanied by bilateral foot drop. Pain sensation was decreased diffusely in upper and lower limbs, and vibration and proprioception were impaired below ankles with positive Romberg sign. Deep tendon reflex was absent in all extremities. He had unequal sized pupils which did not respond to the light. Laboratory tests were unremarkable. Nerve conduction study (NCS) was compatible with diffuse sensorimotor polyneuropathy. Autonomic function test (AFT) represented severe pan-autonomic dysfunction. Transthoracic echocardiography showed a concentric left ventricular hypertrophy with normal left ventricular contractility. Sural nerve biopsy confirmed deposit of amyloid with loss of myelinated nerve fibers. PCR-Sanger sequencing revealed a heterozygous mutation in TTR (p.A56P), which had been reported pathogenic in FAP families. The same mutation was detected in his sister who did not complain any sensorimotor symptoms but occasional orthostatic dizziness; neither NCS nor AFT could detect any abnormality. High awareness is required to diagnose these paucisymptomatic cases before irreversible amyloid accumulation take place.

CHCHD10 is not a frequent causative gene in Chinese ALS patients

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the death of motor neurons. Recently, mutations in CHCHD10 have been reported to cause ALS in Western populations. In the present study, direct DNA sequencing has been performed on CHCHD10 in a cohort of 294 ALS patients of Chinese Han origin. No mutations were identified in CHCHD10 in ALS cases of Chinese ancestry. We propose CHCHD10 might not be a frequent causal gene among Chinese with ALS.

Clinical and genetic features of paroxysmal kinesigenic dyskinesia in Italian patients.

Paroxysmal Kinesigenic Dyskinesia (PKD, OMIM 128200) is the most common type of autosomal dominant Paroxysmal Dyskinesias characterized by attacks of dystonia and choreoathetosis triggered by sudden movements. Recently PRRT2, encoding proline-rich transmembrane protein 2, has been described as the most frequent causative gene for PKD. We studied the incidence of PRRT2 mutations in a cohort of 16 PKD patients and their relatives for a total of 39 individuals. We identify mutations in 10/16 patients and 23 relatives. In 27/33 the mutation was the c.insC649 p.Arg217Profs*8. In 6 individuals from 3 families we found three new mutations: c.insT27 p.Ser9*, c.G967A p.Gly323Arg and c.delCA215_216 p.Thr72Argfs*62. Family history was positive in 9 patients. The mean age of onset was 10 years. Attacks lasted from a few seconds to 1min and ranged from several per day to some per week, and were generalised in all patients. The main distinctive features of mutation-negative patients were the sporadic occurrence, the absence of association with epilepsy or EEG abnormalities and the poor response to Carbamazepine or other antiepileptic agents. We report the first cohort of Italian patients mutated in PRRT2 and we confirm that this is the most frequent gene involved in PKD.

Strategy for the customized mass screening of genetic sensorineural hearing loss in koreans.

Hearing loss is one of the most common sensorineural disorder. More than half of congenital bilateral profound deafness cases have been estimated to be attributed to genetic cause. Identification of genetic cause can provide valuable information. We developed new diagnostic strategy combining phenotype-driven candidate gene approach and targeted exome sequencing to find out the causative mutation of hearing loss. The causative mutation detection rates of this strategy were 78.1% and 54.8% in Korean multiplex families and sporadic severe to profound hearing loss families, respectively. The most frequent causative genes of Korean multiplex families were SLC26A4 and POU3F4. The other causative genes were MRNR1, WFS1, COCH, TECTA, MYO6, COL11A2, EYA4, GJB3, OTOF, STRC, MYO3A, and GJB2. The most frequent causative gene of Korean sporadic severe to profound hearing loss families was SLC26A4 followed by GJB2, CHD7, and CDH23. Based upon the results, the value of this strategy as a diagnostic tool seems to be promising. Although whole genome and exome sequencing have advanced as the development of next-generation sequencing, this new strategy could be a good screening and diagnostic tool to find the causative mutations.

Impaired in vivo dopamine release in parkin knockout mice

parkin is the most frequent causative gene among familial Parkinson's disease (PD). Although parkin deficiency induces autosomal recessive juvenile parkinsonism (AR-JP, PARK2) in humans, parkin knockout (PKO) mice consistently show few signs of dopaminergic degeneration. We aimed to directly measure evoked extracellular dopamine (DA) overflow in the striatum with in vivo voltammetry. The amplitude of evoked DA overflow was low in PKO mice. The half-life time of evoked DA overflow was long in PKO mice suggesting lower release and uptake of dopamine. Facilitation of DA overflow by repetitive stimulation enhanced in the older PKO mice. Decreased dopamine release and uptake in young PKO mice suggest early pre-symptomatic changes in dopamine neurotransmission, while the enhanced facilitation in the older PKO mice may reflect a compensatory adaptation in dopamine function during the late pre-symptomatic phase of Parkinson's disease. Our results showed parkin deficiency may affect DA release in PKO mice, although it does not cause massive nigral degeneration or parkinsonian symptoms as in humans.

Familial amyloid polyneuropathy (Finnish type) in a Japanese family: Clinical features and immunocytochemical studies

Familial amyloid polyneuropathy (FAP: type IV), known as familial amyloidosis of the Finnish type (FAF), is very rare and reported only in a few countries. The gelsolin mutation G654A is most frequent causative gene in FAF family. The clinical phenotype of FAF possesses several neurological characteristics with multiple cranial nerve signs, in addition to a peculiar exanthema of “lichen amyloidosus” and pendulous skin “cutis laxa”, and the carpal tunnel syndrome. We report a new Japanese FAF family presenting bilateral atrophies and fasciculations of the facial muscles and tongue. The patients in our family presented with skin changes as “lichen amyloidosus” and “cutis laxa”. In this FAF family, lichen amyloidosus appeared under sunlight and high temperatures in the summer season every year. Two patients in our family presented with common clinical features of FAF, except for the above laboratory results. Including previous cases and our family, this clinical phenotype is similar to the gelsolin gene mutation (G654A) in FAF family members.