Compound Heterozygous Missense Mutations Research Articles

A case report of adult type 2 familial hemophagocytic lymphohistiocytosis

AbstractFamilial hemophagocytic lymphohistiocytosis (FHL) is a fatal autosomal recessive disorder that often occurs in infants and young children, and rarely reported in adults. In this paper, we retrospectively reported an elderly woman with recurrent fever, this patient was diagnosed with familial hemophagocytic syndrome by perfecting relevant examinations after admission, improvement was observed after standard chemotherapy. In order to further determine the possible underlying genetic causes, we performed gene mutation analysis and found that there were compound heterozygous missense mutations c.133G > A (p.Gly45Arg) and c.147C > A (p.Asp49Glu) on the exon2 of PRF1 gene in this patient. According to the clinical manifestations and test results, the patient was further confirmed as late‐onset FHL‐2 type. Without a suitable donor, the patient did not perform hematopoietic stem cell transplantation. Therefore, the relevant genetic examination should be performed as early as possible in young patients with a family history of hemophagocytic lymphohistiocytosis, and it can provide a basis for etiological diagnosis and radical treatment by hematopoietic stem cell transplantation. It is essential to further study the molecular mechanism and clinical application value for late‐onset elderly FHL patients without appropriate donors.

Identification of genotype–biochemical phenotype correlations associated with fructose 1,6-bisphosphatase deficiency

Fructose-1,6-bisphosphatase (FBPase) deficiency, caused by an FBP1 mutation, is an autosomal recessive disorder characterized by hypoglycemic lactic acidosis. Due to the rarity of FBPase deficiency, the mechanism by which the mutations cause enzyme activity loss still remains unclear. Here we identify compound heterozygous missense mutations of FBP1, c.491G>A (p.G164D) and c.581T>C (p.F194S), in an adult patient with hypoglycemic lactic acidosis. The G164D and F194S FBP1 mutants exhibit decreased FBP1 protein expression and a loss of FBPase enzyme activity. The biochemical phenotypes of all previously reported FBP1 missense mutations in addition to G164D and F194S are classified into three functional categories. Type 1 mutations are located at pivotal residues in enzyme activity motifs and have no effects on protein expression. Type 2 mutations structurally cluster around the substrate binding pocket and are associated with decreased protein expression due to protein misfolding. Type 3 mutations are likely nonpathogenic. These findings demonstrate a key role of protein misfolding in mediating the pathogenesis of FBPase deficiency, particularly for Type 2 mutations. This study provides important insights that certain patients with Type 2 mutations may respond to chaperone molecules.

Rare Compound Heterozygous Missense Mutation of the SCN5A Gene with Childhood-Onset Sick Sinus Syndrome in Two Chinese Sisters.

Sick sinus syndrome (SSS) is a group of syndromes characterized by pathological changes in the sinoatrial node and its adjacent tissues. Although several mutations in the SCN5A gene have been associated with early-onset SSS, pediatric patients are still less common. Here, we report a rare compound missense mutation in the SCN5A gene [c.2893C>T (p. R965C) and c.2431C>T (p. R811C) ] in two sisters with childhood-onset SSS in Chinese population. The proband (5 years and 5 months old) was the second child of a clinically normal and nonconsanguineous couple. Her elder sister was 12 years old and had been implanted with a pacemaker because of the diagnosis of SSS at another hospital one year ago. The proband was presented to the hospital with a slowed heart rate and reduced endurance exercise capacity for more than three months. After a comprehensive clinical examination, she was diagnosed with SSS and underwent pacemaker implantation. Exome and Sanger sequencing were used to determine the compound heterozygous missense mutation of [c.2893C>T (p. R965C) and c.2431C>T (p. R811C) ] in the SCN5A in the patient and her elder sister. Each healthy parent carried a different heterozygous missense mutation. The compound heterozygous mutation of c.2893C>T (p. R965C) and c.2431C>T (p. R811C) rather than the single mutation might be the primary cause of familial early-onset SSS in Chinese population. Our current findings expanded the current understanding of the SCN5A gene mutations. We further confirmed the essential role of the SCN5A gene on the diagnosis, family cascade screening, early intervention, and prognostic evaluation of SSS.

Novel compound heterozygous missense variants in TOE1 gene associated with pontocerebellar hypoplasia type 7

BackgroundPontocerebellar hypoplasia type 7(PCH7)is a neurodegenerative disease related to autosomal recessive variants in the target of EGR1 (TOE1)gene. Biallelic mutation in the TOE1 gene causes global developmental delay, cognitive and psychomotor impairment, hypotonia, breathing abnormalities, and gonadal abnormalities. This study examined the clinical and genetic features of a 2-year-old patient carrying novel compound heterozygous variants in the TOE1 gene, mutations of previously reported 14 PCH7 patients were reviewed. MethodsClinical data of the 2-year-old patient were captured. Trio- whole exome sequencing (Trio-WES) was performed to identify pathogenic variants. Sanger sequencing was further used to verify the variants. In silico analysis was performed to explain the pathogenicity. ResultsHerein, we described the clinical features of the 2-year-old patient diagnosed with PCH7 caused by mutations in the TOE1gene. The kid was presenting with global development delay and gonadal abnormalities. Brain imaging revealed hypoplasia of the cerebellum and pons with ambiguous genitalia. Trio-WES revealed novel compound heterozygous missense variants in TOE1gene (c.911C > T p.S304L, c.161C > T p.A54V). Multiple in silico tools predicted the deleterious effects of the mutations. ConclusionThe novel compound heterozygous missense mutation in the TOE1 gene identified in the proband broadened the genotypic and phenotypic spectrum of disorders associated with PCH7. Our findings provide critical information for the differential diagnosis of rare neurodevelopment disorders and genetic counselling.

Pseudocoloboma-like maculopathy with biallelic RDH12 missense mutations

BackgroundHereditary maculopathy is a group of clinically and genetically heterogeneous disorders. With distinctive clinical features, subtypes of macular atrophy may correlate with their genetic defects.MethodsSeven patients from six families with...

Meta-analysis for the association of GJB2 gene p.V37I variant and its types with the risk of deafness

To assess the association of c.109G>A (p.V37I) variant of the GJB2 gene and its types with the risk of deafness. PubMed, Embase, Cochrane Library, CNKI, Wanfang, and VIP database were searched for cases with GJB2 gene c.109G>A (p.V37I) variant and its compounds with variants of other sites from case-control studies, cohort studies and cross-sectional studies. The search time was from the establishment of database to April 2021. Two researchers have independently screened the literature according to the inclusion and exclusion criteria, extracted the data, and evaluated the included studies according to the criteria. Stata 12.0 software was used for the meta-analysis and publication bias analysis, and a sensitivity analysis was also carried out when necessary. A total of 22 articles (17 in English and 5 in Chinese) were included. There were 7455 cases in the deafness group and 10 464 cases in the control group. The results of meta-analysis showed the c.109G>A (p.V37I) variant to be strongly associated with the risk of deafness (OR: 3.56, 95%CI: 2.31-5.47, P < 0.001). Analysis based on the mutational type also suggested c.109G>A (p.V37I) homozygosity (OR: 11.36, 95%CI: 5.93-21.74, P < 0.001) and compound loss of heterozygosity mutations (OR: 9.27, 95%CI: 3.97-21.64, P < 0.001) to be strongly associated with the risk of deafness. By contrast, heterozygous c.109G>A (p.V37I) variant (OR: 1.20, 95%CI: 0.72-2.00, P = 0.478) and compound heterozygous missense mutation (OR: 1.54, 95%CI: 0.98-2.44, P = 0.063) are not strongly associated with the risk. The homozygous c.109G>A (p.V37I) variants of the GJB2 gene and its compound deletional mutation with another GJB2 allele can significantly increase the risk of deafness. Heterozygous c.109G>A (p.V37I) variant of the GJB2 gene or its compound with a missense mutation of another GJB2 allele do not increase the risk.

Whole exome sequencing identifies causative compound heterozygous variants in PRF1 in late-onset familial hemophagocytic lymphohistiocytosis

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disease in which cells of the immune system are overactivated, leading to uncontrolled inflammation and tissue destruction. Inherited or familial forms of HLH (FHL) are further classified into FHL1 to 5, based on the underlying genetic etiology. The most common form, FHL2, is associated with mutations in the PRF1 gene encoding perforin, a pore-forming glycoprotein required for natural killer and cytotoxic T cell-mediated apoptosis. Importantly, diagnosis of FHL can be challenging, particularly in late-onset cases in which presentation is delayed beyond the first years of life. Aim: We report the essential role of whole exome sequencing in the diagnostic work-up of a patient with complex, late-onset FHL. Methods: A comprehensive retrospective chart review was performed. Results: Our patient presented at 11 years of age with recurrent fever, hepatosplenomegaly, and pancytopenia. In the following years, she was admitted to hospital on multiple occasions, including twice for febrile neutropenia, and once for febrile cytopenia. Serial immune evaluation revealed features of immune dysregulation. While HLH was suspected, she did not fulfil the diagnostic criteria. Initial genetic work-up involving a targeted primary immunodeficiency gene panel identified only a single novel variant of uncertain significance, c.T374C (p.I125T) in PRF1. Subsequently, research-based whole exome sequencing was performed which revealed a second variant, c.C272T (p.A91V), in the same gene. The expanded genetic findings, a set of compound heterozygous missense mutations in PRF1, strengthened the diagnosis of FHL. She later fulfilled the diagnostic criteria for HLH. Conclusion: Whole exome sequencing identified compound heterozygous mutations in the PRF1 gene in a patient with late-onset FHL. Statement of Novelty: We report the use of whole exome sequencing to identify compound heterozygous mutations in PRF1, including a novel p.I125T variant not previously identified in FHL.

Fetal Presentation of Walker-Warburg Syndrome with Compound Heterozygous POMT2 Missense Mutations

Background: Walker-Warburg syndrome (WWS) (OMIM #236670) is an autosomal recessive disorder characterized by congenital muscular dystrophy, hydrocephalus, cobblestone lissencephaly, and retinal dysplasia. The main genes involved are: POMT1, POMT2, POMGNT1, FKTN, LARGE1, and FKRP. Case report: We present a fetus with WWS showing at ultrasound severe triventricular hydrocephalus. Pregnancy was legally terminated at 21 weeks +2 days of gestation. In vivo and postmortem magnetic resonance revealed corpus callosum agenesis and cerebellar hypoplasia. Cobblestone lissencephaly was observed at post-mortem. Next generation sequencing (NGS) of 193 genes, performed on fetal DNA extracted from amniocytes, detected two heterozygous mutations in the POMT2 gene. The c.1238G > C p.(Arg413Pro) mutation was paternally inherited and is known to be pathogenic. The c.553G > A p.(Gly185Arg) mutation was maternally inherited and has not been previously described. Conclusion: Compound heterozygous mutations in the POMT2 gene caused a severe cerebral fetal phenotype diagnosed prenatally at midgestation allowing therapeutic pregnancy termination.

Establishment of a human induced pluripotent stem cell line, KMUGMCi003-A, from a patient with trichothiodystrophy 1 (TTD1) bearing compound heterozygous missense mutations in the ERCC2 gene

Trichothiodystrophy 1 (TTD1) is a rare, autosomal recessive, multisystem disorder characterized by the sulfur-deficient brittle hair, cutaneous photosensitivity, high risk of skin cancer, psychomotor retardation. TTD1 is caused by homozygous or compound heterozygous mutation in ERCC2 gene. The peripheral blood mononuclear cells (PBMCs) from a patient carrying two heterozygous missense mutations of the ERCC2 gene were reprogrammed using the CytoTune-iPS2.0 Sendai Reprogramming Kit. The putative compound heterozygous mutation in ERCC2 will cause the abnormal protein, which is known to associated with TTD1. The established human induced pluripotent cell (hiPSC) line will enable proper in vitro disease modelling of TTD1.

CACNA1A Mutations Associated With Epilepsies and Their Molecular Sub-Regional Implications.

PurposePreviously, mutations in the voltage-gated calcium channel subunit alpha1 A (CACNA1A) gene have been reported to be associated with paroxysmal disorders, typically as episodic ataxia type 2. To determine the relationship between CACNA1A and epilepsies and the role of molecular sub-regional on the phenotypic heterogeneity.MethodsTrio-based whole-exome sequencing was performed in 318 cases with partial epilepsy and 150 cases with generalized epilepsy. We then reviewed all previously reported CACNA1A mutations and analyzed the genotype-phenotype correlations with molecular sub-regional implications.ResultsWe identified 12 CACNA1A mutations in ten unrelated cases of epilepsy, including four de novo null mutations (c.2963_2964insG/p.Gly989Argfs*78, c.3089 + 1G > A, c.4755 + 1G > T, and c.6340-1G > A), four de novo missense mutations (c.203G > T/p.Arg68Leu, c.3965G > A/p.Gly1322Glu, c.5032C > T/p.Arg1678Cys, and c.5393C > T/p.Ser1798Leu), and two pairs of compound heterozygous missense mutations (c.4891A > G/p.Ile1631Val& c.5978C > T/p.Pro1993Leu and c.3233C > T/p.Ser1078Leu&c.6061G > A/p.Glu2021Lys). The eight de novo mutations were evaluated as pathogenic or likely pathogenic mutations according to the criteria of American College of Medical Genetics and Genomics (ACMG). The frequencies of the compound heterozygous CACNA1A mutations identified in this cohort were significantly higher than that in the controls of East Asian and all populations (P = 7.30 × 10–4, P = 2.53 × 10–4). All of the ten cases were ultimately seizure-free after antiepileptic treatment, although frequent epileptic seizures were observed in four cases. Further analysis revealed that episodic ataxia type 2 (EA2) had a tendency of higher frequency of null mutations than epilepsies. The missense mutations in severe epileptic phenotypes were more frequently located in the pore region than those in milder epileptic phenotypes (P = 1.67 × 10–4); de novo mutations in the epilepsy with intellectual disability (ID) had a higher percentage than those in the epilepsy without ID (P = 1.92 × 10–3).ConclusionThis study suggested that CACNA1A mutations were potentially associated with pure epilepsy and the spectrum of epileptic phenotypes potentially ranged from the mild form of epilepsies such as absence epilepsy or partial epilepsy, to the severe form of developmental epileptic encephalopathy. The clinical phenotypes variability is potentially associated with the molecular sub-regional of the mutations.

Disruptions in protein-protein interactions between HTT, PRPF40B, and MECP2 are involved in Lopes-Maciel-Rodan syndrome

Lopes-Maciel-Rodan syndrome (LOMARS) is a rare and serious neurodevelopmental disorder caused by two compound heterozygous missense mutations in the Huntingtin gene (HTT). LOMARS is related to Rett syndrome, which is primarily caused by mutations in X-linked Methyl-CpG-Binding Protein 2 (MECP2), since it results in Rett-like neurological phenotypes and manifestations. While HTT and MECP2 proteins are not known to directly bind to each other, it is plausible that other protein(s) enable and enhance this protein-protein interaction (PPI). This study reports the involvement of pre-mRNA Processing Factor 40 Homolog B (PRPF40B) in mediating the PPI between HTT and MECP2. By using coevolution data, we found that PRPF40B interacts with both HTT and MECP2 through its group II WW domain, a modular protein domain that mediates protein-protein interactions. We also revealed that multiple missense and splice region variants in PRPF40B result in LOMARS and Rett-like phenotypes, suggesting that weakened interactions between mutant PRPF40B and wild-type MECP2 are likely to be associated with the phenotypes. Furthermore, upon docking wild-type and mutant models of HTT with PRPF40B, we observed that the LOMARS-associated mutations significantly weaken HTT-PRPF40B interactions. We also performed similar docking experiments on SIN3A and PRPF40A, which is a protein that is highly related in structure and function to PRPF40B and observed that the mutations also weaken their interactions with HTT. Overall, this study demonstrates the significant role of HTT-PRPF40B-MECP2 interactions in the development and progression of LOMARS and suggests the involvement of similar PPI disruption in Rett syndrome.

Thrombocytopenia Caused By Compound Heterozygous Missense Mutations C.3946G>a in Vwf Gene and C.1825C>T in MYO5A Gene?

Objective: One patient with thrombocytopenia from childhood was examined to identify the cause of thrombocytopenia.Methods: The previous medical history of the patient was comprehensively reviewed, with blood routine examination , reticular platelet count, autoantibodies, hepatitis virus full set, thyroid function, plasma coagulation factor VIII activity, vWF activity and antigen testing, and NGS with peripheral blood to detect thrombosis and hemostatic related genes.Results: The female patient, 43 years old, was presented with thrombocytopenia for more than 40 years. She had no history of fever or bleeding with no significant menstrual volume increasing. His father had similar thrombocytopenia but died four years ago. On third June,2021, she had no skin bruises or enlarged spleen. Blood routine test showed wbc 7.4x10 9/l, HB 112g/l, Plt 47x10 9/l and reticular platelet count 1.85%. Hepatitis B surface antibody was 147.08mIU/ml. FVIII:C was 62.0% with vWF:A 17.4% and vWF:Ag 61.9%. NGS results suggested that there was a heterozygous c.3946G> A missense mutations in Exon28 of vWF gene (chr12:6128638) , resulting in p.Val1316Met. The variation is rare in the East Asian population and is shown in the human disease database to cause type 2B vWD, which causes increased platelet clearance due to variation in vWF molecule-platelet binding regions, clinically manifested as mild to moderate platelet reduction. there was also a heterozygous c.1825C>T missense mutation in Exon15 of MYO5A gene (chr15:52676447) , resulting in p.Arg609Cys. There are adverse effects on the structure / function of the MYH12 protein encoded by the MYO5A gene. The MYH12 protein is involved in cell metabolism and cytoskeletal activity, and this protein deficiency might also cause thrombocytopenia, which is clearly warranted to further investigation.Conclusions：compound heterozygous missense mutations c.3946G>A in vWF gene and c.1825C>T in MYO5A gene might caused thrombocytopenia in the patient. DisclosuresNo relevant conflicts of interest to declare.

Generation of an induced pluripotent stem cell line (DHMCi006-A) from a patient with autosomal recessive polycystic kidney disease (ARPKD) carrying a compound heterozygous missense mutation in the fibrocystin encoding PKHD1 gene

Mutations in the PKHD1 gene, encoding for the ciliary protein fibrocystin, play a major role in the cystogenesis in autosomal recessive polycystic kidney disease (ARPKD), a severe pediatric kidney disorder. Peripheral blood mononuclear cells (PBMCs) from a female patient carrying a compound heterozygous PKHD1 mutation (c.6331A>G(;)7717C>T) were obtained and reprogrammed by viral transduction using the Cytotune®-iPS 2.0 Sendai Reprogramming Kit (Invitrogen). The resulting iPSCs display a normal karyotype, express pluripotency markers, and show the potential for spontaneous differentiation in vitro, offering a useful tool for studying ARPKD pathomechanisms and drug screening.

Novel compound heterozygous missense mutations in GDAP1 cause Charcot–Marie–Tooth type 4A

Homozygous or compound heterozygous mutations in the GDAP1 gene cause Charcot-Marie-Tooth (CMT4A) that are consistent with an autosomal recessive mode of inheritance. The case reported in this study is clinically and genetically diagnosed with recessive CMT4A that is caused by a compound novel heterozygous GDAP1 mutation. The genomic DNA of the proband with the clinical diagnosis of CMT was screened for GDAP1 mutations using a targeted next-generation sequencing (NGS) gene-panel that comprised of 27 CMT genes. Two novel compound heterozygous amino acid changing variants were identified in the GDAP1 gene, c.246C>G p.His82Gln in exon 2 and c.614T>G p.Leu205Trp in exon 5. The two amino acid changing variants were not previously reported in the 1000 Genome, Mutation Taster and gnomAD. Our findings expand the phenotypic characterization of the two novel heterozygous mutations associated with CMT4A (AR-CMT1A) and add to the repertoire of GDAP1 mutations related to autosomal recessive CMT in Chinese populations.

Compound heterozygous missense mutations in a Chinese mucopolysaccharidosis type VI patient: a case report

BackgroundMucopolysaccharidosis type VI (MPS VI) is a rare autosomal recessive inherited disease caused by mutations in the arylsulfatase B (ARSB) gene. MPS VI is a multisystemic disease resulting from a deficiency in arylsulfatase B causing an accumulation of glycosaminoglycans in the tissues and organs of the body.In this report, we present the case of a 16-year-old Chinese male who presented with vision loss caused by corneal opacity. MPS VI was confirmed by genetic diagnosis.Case presentationA 16-year-old Chinese male presented with a one-year history of binocular vision loss. The best-corrected visual acuity was 0.25 in the right eye and 0.5 in the left eye. Although slit-lamp examination revealed corneal opacification in both eyes, the ocular examinations of his parents were normal. At the same time, the patient presented with kyphotic deformity, short stature, joint and skeletal malformation, thick lips, long fingers, and coarse facial features. Genetic assessments revealed that ARSB was the causative gene. Compound heterozygous missense mutations were found in the ARSB gene, namely c.1325G > A (p. Thr442Met) (M1) and c.1197G > C (p. Phe399Leu) (M2). Genetic diagnosis confirmed that the patient had MPS VI.ConclusionsThis paper reports a case of MPS VI confirmed by genetic diagnosis.MPS VI is a multisystem metabolic disease, with corneal opacity as a concomitant ocular symptom. As it is difficult for ophthalmologists to definitively diagnose MPS VI, genetic testing is useful for disease confirmation.

RYR2 Mutations Are Associated With Benign Epilepsy of Childhood With Centrotemporal Spikes With or Without Arrhythmia.

RYR2 encodes ryanodine receptor 2 protein (RYR-2) that is mainly located on endoplasmic reticulum membrane and regulates intracellular calcium concentration. The RYR-2 protein is ubiquitously distributed and highly expressed in the heart and brain. Previous studies have identified the RYR2 mutations in the etiology of arrhythmogenic right ventricular dysplasia 2 and catecholaminergic polymorphic ventricular tachycardia. However, the relationship between RYR2 gene and epilepsy is not determined. In this study, we screened for novel genetic variants in a group of 292 cases (families) with benign epilepsy of childhood with centrotemporal spikes (BECTS) by trio-based whole-exome sequencing. RYR2 mutations were identified in five cases with BECTS, including one heterozygous frameshift mutation (c.14361dup/p.Arg4790Pro fs∗6), two heterozygous missense mutations (c.2353G > A/p.Asp785Asn and c.8574G > A/p.Met2858Ile), and two pairs of compound heterozygous mutations (c.4652A > G/p.Asn1551Ser and c.11693T > C/p.Ile3898Thr, c.7469T > C/p.Val2490Ala and c.12770G > A/p.Arg4257Gln, respectively). Asp785Asn was a de novo missense mutation. All the missense mutations were suggested to be damaging by at least three web-based prediction tools. These mutations do not present or at low minor allele frequency in gnomAD database and present statistically higher frequency in the cohort of BECTS than in the control populations of gnomAD. Asp785Asn, Asn1551Ser, and Ile3898Thr were predicted to affect hydrogen bonds with surrounding amino acids. Three affected individuals had arrhythmia (sinus arrhythmia and occasional atrial premature). The two probands with compound heterozygous missense mutations presented mild cardiac structural abnormalities. Strong evidence from ClinGen Clinical Validity Framework suggested an association between RYR2 variants and epilepsy. This study suggests that RYR2 gene is potentially a candidate pathogenic gene of BECTS. More attention should be paid to epilepsy patients with RYR2 mutations, which were associated with arrhythmia and sudden unexpected death in previous reports.

Toxic accumulation of copper and neuropsychiatric symptoms due to a familial tunisian compound heterozygous ATP7B missense mutation

IntroductionWilson disease (WD) is an autosomal recessive genetic disorder caused by loss-of-function mutations in the P-type copper ATPase, ATP7B (ATPase copper-transporting beta), which transports copper out of cells. It is characterized by toxic accumulation of copper primarily in the liver and brain, leading to liver disorders and/or neuropsychiatric symptoms.ObjectivesHere, we report a Tunisian pedigree associated to familial ATP7B gene mutation.MethodsMedical genetic investigations, and molecular screening of ATP7B gene mutations were performed to a Tunisian three-generation pedigree with eight members having neuropsychiatric symptoms. Molecular genetic testing of the ATP7B 21 exons was carried out by direct sequencing.ResultsA compound heterozygote mutational status of ATP7B with 2 substitutions: p.H1069Q and p.D642H was found. The family originated from the city of Sfax (Tunisia) showed a pronounced amount of consanguinity and eight members affected by WD. All cases derived from consanguineous couples and harbored psychiatric disorders associated or not to neurologic symptoms. Diagnosis of WD was piloted first through the cases harbouring intention tremor in the upper limbs and ataxia associated with psychiatric symptoms.ConclusionsThe first missense mutation p.H1069Q - c.3207C&gt;A (CAC-CAA) (exon 14) is the most commonest mutation in WD associated with late onset neurological conditions in Europe (Natural variantiVAR_000758 dbSNP:rs76151636). The second missense mutation in exon 6 : p.D642H - c.1924G&gt;C (GAC-CAC) (Natural variantiVAR_000713 dbSNP:rs72552285) affects the domain affinity to copper or the folding structure in the cytoplasmic region and decreases the stability, leading to abnormal localization of the protein within cytoplasm and an impairment of protein function.DisclosureNo significant relationships.

Contribution of rare homozygous and compound heterozygous VPS13C missense mutations to dementia with Lewy bodies and Parkinson\u2019s disease

Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are clinically, pathologically and etiologically disorders embedded in the Lewy body disease (LBD) continuum, characterized by neuronal α-synuclein pathology. Rare homozygous and compound heterozygous premature termination codon (PTC) mutations in the Vacuolar Protein Sorting 13 homolog C gene (VPS13C) are associated with early-onset recessive PD. We observed in two siblings with early-onset age (< 45) and autopsy confirmed DLB, compound heterozygous missense mutations in VPS13C, p.Trp395Cys and p.Ala444Pro, inherited from their healthy parents in a recessive manner. In lymphoblast cells of the index patient, the missense mutations reduced VPS13C expression by 90% (p = 0.0002). Subsequent, we performed targeted resequencing of VPS13C in 844 LBD patients and 664 control persons. Using the optimized sequence kernel association test, we obtained a significant association (p = 0.0233) of rare VPS13C genetic variants (minor allele frequency ≤ 1%) with LBD. Among the LBD patients, we identified one patient with homozygous missense mutations and three with compound heterozygous missense mutations in trans position, indicative for recessive inheritance. In four patients with compound heterozygous mutations, we were unable to determine trans position. The frequency of LBD patient carriers of proven recessive compound heterozygous missense mutations is 0.59% (5/844). In autopsy brain tissue of two unrelated LBD patients, the recessive compound heterozygous missense mutations reduced VPS13C expression. Overexpressing of wild type or mutant VPS13C in HeLa or SH-SY5Y cells, demonstrated that the mutations p.Trp395Cys or p.Ala444Pro, abolish the endosomal/lysosomal localization of VPS13C. Overall, our data indicate that rare missense mutations in VPS13C are associated with LBD and recessive compound heterozygous missense mutations might have variable effects on the expression and functioning of VPS13C. We conclude that comparable to the recessive inherited PTC mutations in VPS13C, combinations of rare recessive compound heterozygous missense mutations reduce VPS13C expression and contribute to increased risk of LBD.

Mandibuloacral dysplasia type A in five tunisian patients

Mandibuloacral dysplasia with type A lipodystrophy is a rare autosomal recessive disorder characterized by craniofacial dysmorphism, type A lipodystrophy, clavicular dysplasia, and acroostelolysis. It is caused by homozygous or compound heterozygous missense mutations in LMNA gene. We report five Tunisian patients harboring the same homozygous c.1580G > A; p. (Arg527His) mutation in LMNA gene. The patients presented with typical features of mandibuloacral dysplasia including, prominent eyes, thin or beaked nose, dental overcrowding, mandibular hypoplasia, short and broad finger's distal phalanges with round tips and lipodystrophy type A. Newly recognized signs are growth hormone deficiency and dilated cardiomyopathy. Genotype-phenotype correlation found that at least one of the disease's LMNA mutant alleles involve one of the highly conserved aminoacids, residing in a key site domain for protein function within the C-terminal globular domain of A-type lamins. Also, the severity of the disease depends on the position in the protein's domain and on the type of substitution of the concerned aminoacid.

Anti-Myelin Oligodendrocyte Glycoprotein Encephalomyelitis and Extensive Longitudinal Transverse Myelitis Associated with Compound Heterozygous NLRP3 Missense Mutations in a Young Child

AbstractAcute disseminated encephalomyelitis in association with extensive longitudinal transverse myelitis is reported in a young child with positive anti-myelin oligodendrocyte glycoprotein (MOG) antibody with heterozygous NLRP3 missense mutations; p.(Arg488Lys) and p.(Ser159Ile). This case may well present an exceptional coincidence, but may describe a yet unrecognized feature of the spectrum of childhood onset cryopyrinopathies that contribute to the understanding of the genetic basis for anti-MOG antibody positive encephalomyelitis. Based on this observation, a larger scale study investigating the role of NLRP3 and other inflammasomes in this entity would provide important pathophysiological insights and potentially novel avenues for treatment.