COLQ Mutations Research Articles

Can Scoliosis Help the Early Diagnosis of Congenital Myasthenic Syndrome?

Background Congenital myasthenic syndromes (CMS) are a group of hereditary diseases of the neuromuscular junction. CMS are extremely rare diseases that cause hypotonia; however, scoliosis may theoretically be helpful in early diagnosis of CMS. The objective of this studywas to emphasize the clinical features of the patients we followed up with the diagnosis of CMS and demonstrate that scoliosis is an important finding in the diagnosis of CMS in the presence of hypotonia/weakness. Materials and methods In this retrospective study, data were retrieved by examining the digital files of the patients who presented to Aydın Maternity and Children's Hospital and Elazığ Fethi Sekin City Hospital Pediatric Neurology Clinics between 2018 and 2023. The diagnosis of CMS was strongly supported by a combination of clinical characteristics, neurophysiological studies, genetic tests, AChR antibodies, and serum creatine kinase measurement. The presence of scoliosis was evaluated by an orthopedics and traumatology specialist. Results Eleven CMS patients with accompanying scoliosis were included in the study. The mean age of the patients was 69.4±39.28 months. The age of the patients at the time of diagnosis was 42.7±35.19 months. Among the patients, eight were males (72.7%), and three were females (27.2%). Seven patients (63.6%) had COLQ mutations. Electromyography was conducted on eight patients, with one of them showing no pathological findings, while seven exhibited decremental responses. All patients had ptosis, while six (54.5%) had bulbar signs. Ten patients (90.9%) had weakness. Nine patients (81.8%) experienced frequent recurrent lower respiratory tract infections. Both the patient with CHAT mutation and RAPSN mutation had arthrogryposis. Conclusion In this study, CMS stands out as an essential consideration in the differential diagnosis, particularly when scoliosis accompanies early-onset muscle weakness.

A novel mutation of the COLQ gene causes congenital myasthenic syndromes: A case report

Congenital myasthenic syndromes (CMS) are a group of heterogeneous disorders of the neuromuscular junctions, characterised by fluctuating and fatigable weakness with an early onset. Endplate acetylcholinesterase deficiency (EAD) due to mutations in COLQ is a subtype of CMS whose key clue for diagnosis is repetitive compound muscle action potential (R-CMAP) under nerve conduction studies. In light of the significant overlap of clinical symptoms, misdiagnosis is common for CMS, causing delayed or incorrect treatments. Here, we report a case of CMS due to a novel mutation in COLQ with a typical R-CMAP and discuss the significance of R-CMAP for diagnosis.

First characterization of congenital myasthenic syndrome type 5 in North Africa.

Congenital myasthenic syndromes (CMS) are associated with defects in the structure and the function of neuromuscular junctions. These rare disorders can result from mutations in the collagenic tail of endplate acetylcholinesterase (COLQ) essentially associated with autosomal recessive inheritance. With the lowered cost of genetic testing and increased access to next-generation sequencing, many mutations have been reported to date. In this study we identified the first COLQ homozygous mutation c.1193T>A in the North African population. This study outlines the genetic and phenotypic features of a CMS patient in a Moroccan family. It also describes a novel COLQ missense mutation associated with CMS-5. COLQ mutations are probably underdiagnosed in these North African populations, this is an issue as CMS-5 may be treated with ephedrine, and albuterol. Indeed, patients can seriously benefit and even recover after the treatment that should be planned according to genetic tests and clinical findings.

Quick and long-lasting responsiveness by ephedrine in an adult woman with congenital myasthenic syndrome associated with a novel COLQ mutation. (2928)

Quick and long-lasting responsiveness by ephedrine in an adult woman with congenital myasthenic syndrome associated with a novel COLQ mutation. (2928)

Congenital myasthenic syndrome in China: genetic and myopathological characterization

ObjectiveWe aimed to summarize the clinical, genetic, and myopathological features of a cohort of Chinese patients with congenital myasthenic syndrome, and follow up on therapeutic outcomes.MethodsThe clinical spectrum, mutational frequency of genes, and pathological diagnostic clues of various subtypes of patients with congenital myasthenic syndrome were summarized. Therapeutic effects were followed up.ResultsThirty‐five patients from 29 families were recruited. Ten genes were identified: GFPT1 (27.6%), AGRN (17.2%), CHRNE (17.2%), COLQ (13.8%), GMPPB (6.9%), CHAT, CHRNA1, DOK7, COG7, and SLC25A1 (3.4% each, respectively). Sole limb‐girdle weakness was found in patients with AGRN (1/8) and GFPT1 (7/8) mutations, whereas distal weakness was all observed in patients with AGRN (6/8) mutations. Tubular aggregates were only found in patients with GFPT1 mutations (5/6). The patients with GMPPB mutations (2/2) had decreased alpha‐dystroglycan. Acetylcholinesterase inhibitor therapy resulted in no response or worsened symptoms in patients with COLQ mutations, a diverse response in patients with AGRN mutations, and a good response in patients with other subtypes. Albuterol therapy was effective or harmless in most subtypes. Therapy effects became attenuated with long‐term use in patients with COLQ or AGRN mutations.InterpretationThe genetic distribution of congenital myasthenic syndrome in China is distinct from that of other ethnic origins. The appearance of distal weakness, selective limb‐girdle myasthenic syndrome, tubular aggregates, and decreased alpha‐dystroglycan were indicative of the specific subtypes. Based on the follow‐up findings, we suggest cautious evaluation of the long‐term efficacy of therapeutic agents in congenital myasthenic syndrome.

Generation of a human induced pluripotent stem cell line (iPSC) from peripheral blood mononuclear cells of a patient with a myasthenic syndrome due to mutation in COLQ

Congenital myasthenic syndromes (CMS) are a class of inherited disorders affecting the neuromuscular junction, a synapse whose activity is essential for movement. CMS with acetylcholinesterase (AChE) deficiency are caused by mutations in COLQ, a collagen that anchors AChE in the synapse. To study the pathophysiological mechanisms of the disease in human cells, we have generated iPSC from a patient's Peripheral Blood Mononuclear cells (PBMC) by reprogramming these cells using a non-integrative method using Sendai viruses bearing the four Yamanaka factors Oct3/4, Sox2, Klf4, and L-Myc.

Congenital myasthenic syndromes in the Thai population: Clinical findings and novel mutations

Congenital myasthenic syndromes (CMS) comprise a heterogeneous group of genetic disorders of the neuromuscular junction. Next generation sequencing has been increasingly used for molecular diagnosis in CMS patients. This study aimed to identify the disease-causing variants in Thai patients. We recruited patients with a diagnosis of CMS based on clinical and electrophysiologic findings, and whole exome sequencing was performed. Thirteen patients aged from 2 to 54 years (median: 8 years) from 12 families were enrolled. Variants were identified in 9 of 13 patients (69%). Five novel variants and two previously reported variant were found in the COLQ, RAPSN and CHRND gene. The previously reported c.393+1G>A splice site variant in the COLQ gene was found in a majority of patients. Five patients harbor the homozygous splice site c.393+1G>A variant, and two patients carry compound heterozygous c.393+1G>A, c.718–1G>T, and c.393+1G>A, c.865G>T (p.Gly289Ter) variants. The novel variants were also found in RAPSN (p.Cys251del, p.Arg282Cys) and CHRND (p.Met481del). Molecular diagnosis in CMS patients can guide treatment decisions and may be life changing, especially in patients with COLQ mutations.

Congenital myasthenic syndrome: Ten years clinical experience from a quaternary care south-Indian hospital

BackgroundTo ascertain the frequency, clinical spectrum and outcome of congenital myasthenic syndrome (CMS) patients who reported to the neuromuscular division of our quaternary medical center during the past ten years. MethodsWe performed a retrospective analysis of all the CMS patients who reported to us during the study period. ResultsTwenty-one patients of CMS attended our quaternary hospital over the past ten years. The median follow-up was 24 (IQR: 16.5–67.3) months. All the patients showed an overall improvement in the last follow up. The diagnosis of CMS could be genetically confirmed in seven cases. Four patients had COLQ mutation, two had CHRNε mutation and one had MUSK mutation. All the cases of COLQ mutation and one case of MUSK mutation had a limb-girdle (LG) presentation. Our study and review of literature imply that CMS should be suspected in cases of seronegative myasthenia gravis cases if the onset is at less than 20 years and strongly so if the onset is within the first two years of life. In addition, a positive family history, delayed motor milestones, and a poor response to immune-modulators should be actively sought for as indicators of CMS.

Congenital myasthenic syndrome in Turkey: clinical and genetic features in the long-term follow-up of patients.

Congenital Myasthenic Syndromes (CMS) are rare disorders that occur as a result of defects in the structure and in the function of neuromuscular junctions. Molecular genetic diagnosis is important to select the most suitable therapeutic option and treatment. Eight patients with congenital myasthenic syndromes who presented to the Çukurova University Pediatric Neurology Department Outpatient Clinic between June 2015 and May 2018 were reviewed. Mutations in the acetylcholine receptor (subunits in epsilon) (CHRNE) in three and mutations in the collagenic tail of endplate acetylcholinesterase (COLQ) gene in five patients were identified; p.W148 mutation was detected to be homozygous in four, c.1169A > G novel mutation in COLQ gene was homozygous in one, c452_454delAGG mutation was homozygous in the other patient, IVS7 + 2T > C(c.802 + 2T > C) mutation was homozygous in a patient and compound heterozygous mutations of c.865C > T(p.Leu289Phe) and c.872C > G(p.A2916)(p.Arg291Gly) in the CHRNE gene in the last patient. The parents of all the evaluated patients were consanguineous. Ptosis, ophthalmoplegia, generalized hypotonia, bulbar weakness, and respiratory crisis were the main findings at the time of presentation. Pyridostigmine is the first-line drug therapy in primary AChR deficiency. Beta adrenergic agonists, ephedrine, and albuterol are the other treatment options for CMS subtypes caused by mutations in COLQ. This study points out the genetic and phenotypic features of CMS patients in the Turkish population and it also reports previously unreported mutations in the literature. CHRNE and COLQ gene mutations are common in the Turkish population. Patients can get serious benefits and recover after the treatment. The treatment should be planned according to genetic tests and clinical findings.

Congenital myasthenic syndrome in Golden Retrievers is associated with a novel COLQ mutation.

BackgroundCongenital myasthenic syndromes (CMSs) are a group of inherited disorders of neuromuscular transmission that may be presynaptic, synaptic, or postsynaptic. Causative mutations have been identified in 4 breeds including the Labrador Retriever, Jack Russell Terrier, Heideterrier, and Danish Pointing Dog.Hypothesis/ObjectiveClinical and genetic characterization of a neuromuscular disorder in Golden Retriever (GR) puppies.AnimalsFour GR puppies from California were evaluated for generalized muscle weakness beginning at weaning. Biological specimens were collected from the affected puppies, and familial information was obtained. Blood or buccal swabs were obtained from 63 unaffected GRs.MethodsComplete physical, neurological, electrodiagnostic, and histological evaluations and biochemical quantification of muscle acetylcholine receptors were performed. Polymerase chain reaction was used to amplify the 17 exons of COLQ, and sequences were obtained by Sanger sequencing. Variant frequency was assessed in unrelated GRs and a public database.ResultsClinical, neurological, and electrodiagnostic evaluations confirmed a disorder of neuromuscular transmission in a GR family. Sequencing of all exons and splice sites of a primary candidate gene, COLQ, identified a point mutation that predicts an amino acid substitution (G294R). The primary COLQ transcript was absent from affected muscle samples. All affected puppies were homozygous for the mutation, which was not detected outside this GR family or in other breeds.Conclusions and Clinical ImportanceWe confirmed the diagnosis of a CMS in GR puppies and identified a novel COLQ mutation. The COLQ gene encodes the collagenous tail of acetylcholinesterase, the enzyme responsible for termination of skeletal muscle contraction by clearing acetylcholine at the neuromuscular junction. Clinicians and breeders should be aware of this CMS in GR puppies with an early onset of weakness.

Congenital myathenic syndrome associated with COLQ mutation: an interesting report

Congenital myasthenic syndromes (CMS) are a rare inherited disorder of neuromuscular transmission associated with abnormal weakness and fatiguability on exertion. Usually present from birth/childhood and are characterized by exercise induced weakness and easy fatigability (regular activities). We present rare and interesting case of CMS. A 26 year old male, born out of non-consanguinous marriage with normal birth history, presented to us with motor developmental delay, was a floppy infant with poor suck and cry with bilateral ptosis, gradually progressive bilateral lower limb weakness since 10 years of age, bilateral upper limb weakness since 12 years of age with easy fatiguability on exertion, ptosis, neck weakness without any fasciculations, bladder bowel involvement or sensory complaints with a negative history family with a worsening of symptoms on pyridostigmine trial. Routine nerve conduction studies were normal. There was decremental response in RNST. His Ach receptor antibody and Musk antibody status were negative. In view of above findings he was subjected to genetic analysis where targeted gene sequencing was done, which revealed a homozygous mutation in the intron 12 of COLQ gene which was pathogenic. The COLQ gene is located at the short arm of chromosome 3. Its AR mutation causes synaptic form of CMS. The age of presentation is variable from early childhood to 4–5th decade with fatiguable weakness, ptosis and respiratory crises. They have variable response to treatment and hence genetic characterization is of utmost importance!

Cardiac autonomic function evaluation in pediatric and adult patients with congenital myasthenic syndromes

Cardiac autonomic dysfunction has been examined in myasthenia gravis but not in congenital myasthenic syndromes (CMS). We aimed to evaluate cardiac autonomic functions in genetically defined CMS. Patients diagnosed with and under treatment for CMS were reviewed for 24-hour cardiac rhythm monitoring. Heart rate variability (HRV) measures were defined as: SDNN, mean of the standard deviations for all R-R intervals; SDNNi, standard deviation of all R-R intervals in successive five-minute epochs; RMSSD, square root of the mean of squared differences between successive R-R intervals. Ten patients with mutations in the epsilon subunit of the acetylcholine receptor (AChRε) and five patients with mutations in the collagen-like tail of asymmetric acetylcholinesterase (ColQ) were included. Median age at evaluation was 17 (2.5–46) years. In the AChRε group, RMSSD values; and in the ColQ group, SDNN, SDNNi and RMSSD values were significantly lower than those of healthy subjects. This first extensive report examining HRV in CMS showed alterations in patients with ColQ mutations and, to a lesser extent, in the group with AChRε mutations. This might indicate an increased risk of cardiac arrhythmias. We suggest cardiological follow-up in CMS, and consideration of any potential cardiovascular effects of therapeutic agents used in management.

CONGENITAL MYASTHENIC SYNDROMES AND MYASTHENIA: P.73Characterization of an Indian congenital myasthenic syndrome cohort by whole exome sequencing

Congenital myasthenic syndromes (CMS) are caused by mutations in genes coding for proteins involved in the maintenance of the neuromuscular junction (NMJ). The patients can be effectively treated and prognosis can be improved when the precise genetic cause is known. In addition, the frequency of the different CMS-causing genes varies with ethnic and geographic origin. There are only few reports from India describing the occurrence of DOK7, RAPSN and COLQ mutations based on selective or limited genetic testing, but the prevalence of various gene mutations in the Indian CMS population is unknown, hence, limiting the effective gene screening and thus, prognosis and access to treatments. DNA from 40 genetically undiagnosed CMS families (total of 87 samples) were subjected to whole exome sequencing (WES). Of those eight families were known to be consanguineous, and majority of them had recessive inheritance pattern.WES was performed using Illumina exome capture (38 Mb target). Data analysis was carried out on the Seqr Genome Analysis Platform. Standard filtering criteria were moderate to high VEP (variant effect predictor), MAF of 0.01(1%) and CADD >20.We identified four GFPT1, four DPAGT1, three COLQ, two MUSK, one CHRND and one SLC25A1 variants that we consider as likely disease-causing. All the variants were highly pathogenic and majority of variants were absent in the control population. The overall solved rate after initial screening for known CMS genes was 37.5% cases (15 out of 40). Interestingly, there was occurrence of rare forms of CMS in the present cohort, and several recurrent mutations seen in COLQ, MUSK and DPAGT1 genes. These mutations might be hot-spots or founder mutations in Indian populations. The remaining patients will undergo further analysis for novel candidate genes.

Mechanism hypotheses for the electrophysiological manifestations of two cases of endplate acetylcholinesterase deficiency related congenital myasthenic syndrome

ObjectiveTo summarize the electrophysiological characteristics of two cases of endplate acetylcholinesterase deficiency (EAD) related congenital myasthenic syndrome (CMS) caused by COLQ mutation and to discuss the possible mechanism of these electrophysiological phenomena. MethodsElectrophysiological examinations were conducted including nerve conduction studies, routine electromyography (EMG), repetitive nerve stimulation (RNS) and single fiber EMG (SFEMG). The ulnar nerve was also stimulated at 50 Hz followed by 0.5 Hz to record the recovery process of compound muscle action potential (CMAP). ResultsRepetitive CMAP (R-CMAP) was found in motor nerve conduction in both cases. Needle EMG showed myogenic damages and SFEMG showed remarkably increased jitter values. Of note, the amplitude of CMAP and R-CMAP showed regular changing trends, and so did their time intervals in RNS studies. ConclusionsThe change patterns of CMAP and R-CMAP, in combination with other electrophysiological features are very useful for the diagnosis of EAD related CMS, especially in predicting the presence of correct gene mutations.

P.415 - Congenital myasthenia syndromes: clinical description of a pediatric cohort

Congenital myasthenic syndromes (CMS) are a group of heterogeneous diseases caused by mutations in genes encoding for proteins involved in the neuromuscular junction that lead to an impaired signal transmission. We describe the clinical and paraclinical history of 12 patients with genetically confirmed CMS (1 CHRND, 2 AGRN, 1 DOK7, 1 MUSK, 4 RAPSN, 1 DPAGT1, 2 COLQ). Fatigable weakness was mentioned in all patients. The first symptom appeared at the latest in the first month of life (extremes: antenatal to less than 1 month of life). 4 patients had neonatal stridor. 11 patients had at least one severe respiratory decompensation with intubation. 8 had been tracheotomized. One patient died (COLQ mutation). 5 patients had arthrogryposis, 1 postural syndrome. Ptosis was reported in 11 patients. 9 of 10 patients who had reached the age of gait walked, (average age: 40 months; median age: 24 months). All patients with RAPSN mutation had clinodactyly. Electromyographic analysis showed neuromuscular junction abnormalities in 9 of 11 patients. Stimulated single fiber was always abnormal (done in 5 patients). Muscle biopsy exhibited mainly type 1 fibers predominance. Histology study of motor endplate performed in 2 patients was abnormal. Diagnostic delay was 35 months on average with a median at 9 months. From a therapeutic point of view, patients with mutations in the RAPSN gene were all significantly improved by anticholinesterasic monotherapy. A bi or triple therapy was required in the others (anticholinesterase, salbutamol / ephedrine, 3–4 DAP). Anticholinesterase drugs aggravated myasthenic syndrome in 3 patients (AGRN, DOK7 and COLQ mutations). The diagnosis of SMC is challenging due to life threatening complications, especially since a specific treatment exists.

Congenital myasthenic syndrome in Israel: Genetic and clinical characterization

The objective of the study was to evaluate the epidemiology of patients with congenital myasthenic syndrome (CMS) in Israel. Targeted mutation analysis was performed based on the clinical symptoms and electrophysiological findings for known CMS. Additional specific tests were performed in patients of Iranian and/or Iraqi Jewish origin. All medical records were reviewed and clinical data, genetic mutations and outcomes were recorded. Forty-five patients with genetic mutations in known CMS genes from 35 families were identified. Mutations in RAPSN were identified in 13 kinships in Israel. The most common mutation was c.-38A>G detected in 8 patients of Iranian and/or Iraqi Jewish origin. Four different recessive mutations in COLQ were identified in 11 kinships, 10 of which were of Muslim-Arab descent. Mutations in CHRNE were identified in 7 kinships. Less commonly detected mutations were in CHRND, CHAT, GFPT1 and DOK7. In conclusion, mutations in RAPSN and COLQ are the most common causes of CMS in our cohort. Specific mutations in COLQ, RAPSN, and CHRNE occur in specific ethnic populations and should be taken into account when the diagnosis of a CMS is suspected.

P.75 - Congenital myasthenic syndrome due to COLQ mutations: Clues for diagnosis

Congenital myasthenic syndromes (CMS) represent a diverse group of genetic disorders caused by abnormal signal transmission at the motor endplate. There is a wide list of differential diagnoses. Specific diagnosis of some CMS can be reached by phenotypic clues. We reviewed clinical presentation and phenotype of our six unrelated patients with homozygous single nucleotide substitution mutation (c.444G > A) in the exon 6 of COLQ gene. Age at presentation of our patients (4 girls, 2 boys) was newborn period (n = 2), 3 months (n = 2), 6 months (n = 1), and infancy period (n = 1). All patients had delayed motor milestones and ptosis, combined with respiratory crises and episodic apneas (n = 4), axial hypotonia and weakness (n = 4), facial and proximal weakness (n = 2), dysphagia (n = 2), and a negative response to acetylcholinesterase inhibitors (n = 3). Electromyographic evaluation was performed in three of the patients, and was compatible with CMS. All patients had homozygous single nucleotide substitution mutation W148X (c.444G > A) in exon 6 of COLQ gene. There has been a treatment response to salbutamol (n = 4), and 3–4 diaminopyridine and/or albuterol (n = 2). Specific diagnosis of ColQ CMS can be reached by clues such as sudden episodic apneas leading to respiratory crisis, CMS refractory or worsened by acetylcholinesterase inhibitors. Our patients represent a wide range of spectrum in terms of disease progression and functional impairment. W148X mutation appears to be a frequent mutation in our population.

COLQ Mutation in Three Siblings of a Saudi Family: Congenital Myasthenia with Phenotypic Heterogeneity and Varying Ages of Onset (P3.139)

COLQ Mutation in Three Siblings of a Saudi Family: Congenital Myasthenia with Phenotypic Heterogeneity and Varying Ages of Onset (P3.139)

Neuromuscular junction immaturity and muscle atrophy are hallmarks of the ColQ‐deficient mouse, a model of congenital myasthenic syndrome with acetylcholinesterase deficiency

The collagen ColQ anchors acetylcholinesterase (AChE) in the synaptic cleft of the neuromuscular junction (NMJ). It also binds MuSK and perlecan/dystroglycan, 2 signaling platforms of the postsynaptic domain. Mutations in ColQ cause a congenital myasthenic syndrome (CMS) with AChE deficiency. Because the absence of AChE does not fully explain the complexity of the syndrome and there is no curative treatment for the disease, we explored additional potential targets of ColQ by conducting a large genetic screening of ColQ-deficient mice, a model for CMS with AChE deficiency, and analyzed their NMJ and muscle phenotypes. We demonstrated that ColQ controls the development and the maturation of the postsynaptic domain by regulating synaptic gene expression. Notably, ColQ deficiency leads to an up-regulation of the 5 subunits of the nicotinic acetylcholine receptor (AChR), leading to mixed mature and immature AChRs at the NMJ of adult mice. ColQ also regulates the expression of extracellular matrix (ECM) components. However, whereas the ECM mRNAs were down-regulated in vitro, compensation seemed to occur in vivo to maintain normal levels of these mRNAs. Finally, ColQ deficiency leads to a general atrophic phenotype and hypoplasia that affect fast muscles. This study points to new specific hallmarks for this CMS.-Sigoillot, S. M., Bourgeois, F., Karmouch, J., Molgó, J., Dobbertin, A., Chevalier, C., Houlgatte, R., Léger, J., Legay, C. Neuromuscular junction immaturity and muscle atrophy are hallmarks of the ColQ-deficient mouse, a model of congenital myasthenic syndrome with acetylcholinesterase deficiency.

G.P.83 - Congenital myasthenic syndromes in Israel: Genetic and clinical characterization

The genetic and clinical characteristics of Israeli patients with congenital myasthenic syndromes (CMS) evaluated in four medical centers are presented. Forty-one patients with CMS from thirty two independent families in whom genetic mutation was detected are described. Genetic evaluation was initially performed depending on patients' clinical symptoms and known CMS genes were sequenced. All patients' medical records were reviewed and their clinical data, electrophysiological studies, genetic mutation and outcome were recorded. Mutations in Rapsyn were detected in 15 patients of 13 families. The most common mutation was the Rap-38A>G, identified in patients of Iran–Iraq Jewish origin. Mutations in COLQ were confirmed in 11 patients of 8 families. Four different recessive mutations of COLQ were identified mostly in Arab patients. CHRNE mutations were confirmed in 15 patients of 13 families. The less common detected mutations were: CHRND, ChAT, GFTP1 and dok-7. The vast majority of children had clinical symptoms in infancy. Ptosis, ophthalmoplegia and feeding problems were the most common symptoms. RAPSYN, COLQ and CHRNE were the most common causes of CMS in our cohort. Specific mutations in these genes are detected in unique ethnic populations in Israel.