Inheritance Pattern Of Disease Research Articles

A novel mutation alters GNE bifunctional enzyme activity and leads to familial inherited GNE diseases

Distal myopathies are a group of rare heterogeneous diseases that are mostly caused by genetic factors. At least 20 genes have been associated with distal myopathies. We performed whole-exome sequencing to identify the genetic cause of disease in a family with distal myopathy. Following the American College of Medical Genetics and Genomics (ACMG) guidelines, we analyzed the sequencing results and screened suspicious mutations based on mutation frequency, functional impact, and disease inheritance pattern. The harmfulness of the mutations was predicted using bioinformatics methods, and the pathogenic mutations were determined. We identified a novel amino acid mutation (NP_005467.1:p.S663L) on the GNE gene that may cause familial distal myopathy. This mutation is the result of the simultaneous mutation of two adjacent nucleotides (c.1988C > T, c.1989C > A) in the codon. First, we measured the mRNA and protein expression of the GNE gene in the lymphoblastoid cell lines (LCLs) of the probands and their family members. Second, GNE vectors carrying the novel mutation, two other known pathogenic mutations, and the wild-type gene were constructed and transfected into HEK293T cells. The enzymatic activity of these GNE variants was investigated and showed that the p.S663L mutation significantly reduced the activity of the bifunctional GNE enzyme without altering the expression level of the GNE protein. Furthermore, the mutation may also alter the immunogenicity of the 3′ end of the GNE protein, potentially affecting its oligomer formation. In this study, a novel GNE gene mutation that may cause distal myopathy was identified, expanding the spectrum of genetic mutations associated with this disease.

Foundational and Clinical Science Integration in a Team-Based Learning Module Modeling Care of a Patient With Dyslipidemia.

Foundational and clinical science integration, a long-standing goal of undergraduate medical education, benefits learners by promoting retention of critical knowledge and skills as well as their transfer to the clinical setting. We implemented a team-based learning (TBL) module in which foundational knowledge and skills from the disciplines of biochemistry, nutrition, and genetics were leveraged in a simulated patient encounter for diagnosis and management of a patient with dyslipidemia. The TBL was deployed in a first-year medical student cardiovascular system course with 125 students over three academic years. Following individual and team readiness assurance tests (iRAT and tRAT, respectively), teams participated in an initial application exercise requiring consideration of clinical and laboratory data and other risk factors to engage the patient in a shared decision-making process. Using dietary and family history narratives in subsequent application exercises, teams completed recommendations for an individualized diet plan and an assessment of potential disease inheritance patterns to formulate appropriate patient care management strategies. Student engagement with prelearning materials and session team activities was high as judged by RAT performance and application exercise outcomes: iRAT question performance ranged from 89% to 99% for individual items, and tRAT performance was routinely 100%. Learners reported that the exercises were impactful and believed the learned foundational knowledge and skills were transferable to future patient care. The dyslipidemia TBL module provides an illustration for early clinical learners of how foundational knowledge and skills can be operationalized and transferred for optimal patient care.

Explicable prioritization of genetic variants by integration of rule-based and machine learning algorithms for diagnosis of rare Mendelian disorders

BackgroundIn the process of finding the causative variant of rare diseases, accurate assessment and prioritization of genetic variants is essential. Previous variant prioritization tools mainly depend on the in-silico prediction of the pathogenicity of variants, which results in low sensitivity and difficulty in interpreting the prioritization result. In this study, we propose an explainable algorithm for variant prioritization, named 3ASC, with higher sensitivity and ability to annotate evidence used for prioritization. 3ASC annotates each variant with the 28 criteria defined by the ACMG/AMP genome interpretation guidelines and features related to the clinical interpretation of the variants. The system can explain the result based on annotated evidence and feature contributions.ResultsWe trained various machine learning algorithms using in-house patient data. The performance of variant ranking was assessed using the recall rate of identifying causative variants in the top-ranked variants. The best practice model was a random forest classifier that showed top 1 recall of 85.6% and top 3 recall of 94.4%. The 3ASC annotates the ACMG/AMP criteria for each genetic variant of a patient so that clinical geneticists can interpret the result as in the CAGI6 SickKids challenge. In the challenge, 3ASC identified causal genes for 10 out of 14 patient cases, with evidence of decreased gene expression for 6 cases. Among them, two genes (HDAC8 and CASK) had decreased gene expression profiles confirmed by transcriptome data.Conclusions3ASC can prioritize genetic variants with higher sensitivity compared to previous methods by integrating various features related to clinical interpretation, including features related to false positive risk such as quality control and disease inheritance pattern. The system allows interpretation of each variant based on the ACMG/AMP criteria and feature contribution assessed using explainable AI techniques.

Genetics of downy mildew resistance in indigenous cucumber germplasm

Cucumber (Cucumis sativus L.) is a major Cucurbitaceous vegetable crop widely grown in tropical andsubtropical regions of the world. Downy mildew is the most damaging disease in cucumber worldwide causingsignificant yield loss. The wide diversity in terms of different economically important traits including severityto downy mildew infestation is available in Indian-originated germplasm. To investigate the genetic inheritanceof cucumber downy mildew disease resistance, one resistant genotype (DC-70) from India was crossed with acontrasting susceptible genotype (DC-773). The parents and their progenies were evaluated in both field andnet house conditions for downy mildew disease resistance. Field condition data were recorded 4-times from30 days until the plants die. The lower leaf surface was inoculated 20-25 days after sowing at the seedlingstage by spraying the inoculum. The proportion of infection was recorded 4-times from 8-days to 65-daysafter inoculation, and the per cent disease index and area under the disease progress curve (AUDPC) werecalculated from these proportions. Based on the PDI and AUDPC, it was established that resistance to downymildew in the genotype, DC-70 was controlled by a major gene. Additive-dominance model fits the segregationdata and the additive effect was significant. Finally, the downy mildew disease inheritance pattern indicatedthat it is controlled by a single recessive gene in DC-70, which can be successfully introgressed into desiredelite genotypes to facilitate the downy mildew resistance breeding programme.

A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders.

Genetic disorders of the skeleton encompass a diverse group of bone diseases differing in clinical characteristics, severity, incidence and molecular etiology. Of particular interest are the monogenic rare bone mass disorders, with the underlying genetic defect contributing to either low or high bone mass phenotype. Extensive, deep phenotyping coupled with high-throughput, cost-effective genotyping is crucial in the characterization and diagnosis of affected individuals. Massive parallel sequencing efforts have been instrumental in the discovery of novel causal genes that merit functional validation using in vitro and ex vivo cell-based techniques, and in vivo models, mainly mice and zebrafish. These translational models also serve as an excellent platform for therapeutic discovery, bridging the gap between basic science research and the clinic. Altogether, genetic studies of monogenic rare bone mass disorders have broadened our knowledge on molecular signaling pathways coordinating bone development and metabolism, disease inheritance patterns, development of new and improved bone biomarkers, and identification of novel drug targets. In this comprehensive review we describe approaches to further enhance the innovative processes taking discoveries from clinic to bench, and then back to clinic in rare bone mass disorders. We highlight the importance of cross laboratory collaboration to perform functional validation in multiple model systems after identification of a novel disease gene. We describe the monogenic forms of rare low and high rare bone mass disorders known to date, provide a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders using proper phenotyping and genotyping methods, and describe different genetic validation approaches paving the way for future treatments.

Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn\u2019s Disease

Inflammatory bowel disease (IBD), clinically defined as Crohn’s disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥ 25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. However, its role in pediatric onset IBD is not well understood. We performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0–18.5 years). We identified 92 probands with biallelic rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from a large clinical population cohort. We found that recessive inheritance of NOD2 variants explains ~ 7% of cases in this adult IBD cohort, including ~ 10% of CD cases, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that several of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. While it has been previously reported that carriers of more than one NOD2 risk alleles have increased susceptibility to Crohn’s Disease (CD), our data formally demonstrate that recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7–10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohn’s Disease.

Ancestral haplotype reconstruction in endogamous populations using identity-by-descent.

In this work we develop a novel algorithm for reconstructing the genomes of ancestral individuals, given genotype or sequence data from contemporary individuals and an extended pedigree of family relationships. A pedigree with complete genomes for every individual enables the study of allele frequency dynamics and haplotype diversity across generations, including deviations from neutrality such as transmission distortion. When studying heritable diseases, ancestral haplotypes can be used to augment genome-wide association studies and track disease inheritance patterns. The building blocks of our reconstruction algorithm are segments of Identity-By-Descent (IBD) shared between two or more genotyped individuals. The method alternates between identifying a source for each IBD segment and assembling IBD segments placed within each ancestral individual. Unlike previous approaches, our method is able to accommodate complex pedigree structures with hundreds of individuals genotyped at millions of SNPs.We apply our method to an Old Order Amish pedigree from Lancaster, Pennsylvania, whose founders came to North America from Europe during the early 18th century. The pedigree includes 1338 individuals from the past 12 generations, 394 with genotype data. The motivation for reconstruction is to understand the genetic basis of diseases segregating in the family through tracking haplotype transmission over time. Using our algorithm thread, we are able to reconstruct an average of 224 ancestral individuals per chromosome. For these ancestral individuals, on average we reconstruct 79% of their haplotypes. We also identify a region on chromosome 16 that is difficult to reconstruct—we find that this region harbors a short Amish-specific copy number variation and the gene HYDIN. thread was developed for endogamous populations, but can be applied to any extensive pedigree with the recent generations genotyped. We anticipate that this type of practical ancestral reconstruction will become more common and necessary to understand rare and complex heritable diseases in extended families.

Mutations Causing Mild or No Structural Damage in Interfaces of Multimerization of the Fibrinogen γ-Module More Likely Confer Negative Dominant Behaviors.

Different pathogenic variants in the same protein or even within the same domain of a protein may differ in their patterns of disease inheritance, with some of the variants behaving as negative dominant and others as autosomal recessive mutations. Here is presented a structural analysis and comparison of the molecular characteristics of the sites in fibrinogen γ-module, a fibrinogen component critical in multimerization processes, targeted by pathogenic variants (HGMD database) and by variants found in the healthy population (gnomAD database). The main result of this study is the identification of the molecular pathogenic mechanisms defining which pattern of disease inheritance is selected by mutations at the crossroad of autosomal recessive and negative dominant modalities. The observations in this analysis also warn about the possibility that several variants reported in the non-pathogenic gnomAD database might indeed be a hidden source of diseases with autosomal recessive inheritance or requiring a combination with other disease-causing mutations. Disease presentation might remain mostly unrevealed simply because the very low variant frequency rarely results in biallelic pathogenic mutations or the coupling with mutations in other genes contributing to the same disease. The results here presented provide hints for a deeper search of pathogenic mechanisms and modalities of disease inheritance for protein mutants participating in multimerization phenomena.

Constraint and conservation of paired-type homeodomains predicts the clinical outcome of missense variants of uncertain significance.

The need to interpret thepathogenicity of novel missense variants of unknown significance identified in the homeodomain of X-chromosome aristaless-related homeobox (ARX) gene prompted us to assess the utility of conservation and constraint across these domains in multiple genes compared to conventional in vitro functional analysis. Pathogenic missense variants clustered in the homeodomain of ARX contribute to intellectual disability (ID) and epilepsy, with and without brain malformation in affected males. Here we report novel c.1112G>A, p.Arg371Gln and c.1150C>T, p.Arg384Cys variants in male patients with ID and severe seizures. The third case of a male patient with a c.1109C>T, p.Ala370Val variant is perhaps the first example of ID and autism spectrum disorder (ASD), without seizures or brain malformation. We compiled data sets of pathogenic variants from ClinVar and presumed benign variation from gnomAD and demonstrated that the high levels of sequence conservation and constraint of benign variation within the homeodomain impacts upon the ability of publicly available in silico prediction tools to accurately discern likely benign from likely pathogenic variants in these data sets. Despite this, considering the inheritance patterns of the genes and disease variants with the conservation and constraint of disease variants affecting the homeodomain in conjunction with current clinical assessments may assist in predicting the pathogenicity of missense variants, particularly for genes with autosomal recessive and X-linked patterns of disease inheritance, such as ARX. In vitro functional analysis demonstrates that the transcriptional activity of all three variants wasdiminished compared to ARX-Wt. We review the associated phenotypes of the published cases of patients with ARX homeodomain variants and propose expansion of the ARX-related phenotype to include severe ID and ASD without brain malformations or seizures. We propose that the use of the constraint and conservation data in conjunction with consideration of the patient phenotype and inheritance pattern may negate the need for the experimental functional validation currently required to achieve a diagnosis.

Profil Pohon Keluarga (Pedigree) Siswa Dengan Intellectual Disability (Id) Dan Multiple Congenital Anomaly (MCA) Di SLB Negeri Kendal

Pedigree construction is one of the ways to seek the inheritance pattern of disease. Three generations pedigree has many benefit in genetic counseling session particularly in establishing a specific inheritance pattern such as autosomal recessive or dominant. This research aimed to analyze three generations pedigree in the family of ID and MCA patients in the Special school of Kendal. This is a descriptive observational study using the interview method in 33 student guardians or parents of ID and MCA students. Twenty-five of 33 respondents collects the complete data. This study showed that three generations of pedigree construction of 8 respondents could not conclude the inheritance pattern. The data showed that two pedigree are suspect of chromosomal abnormalities in the presence of family history with similar disorder, family history with ID and MCA, and family history with IUFD or stillbirth. Further investigation using cytogenetics, FISH, and microarray is needed to establish the diagnosis

The Genetic Multiplicity- Multiple Endocrine Neoplasia type I

Multiple endocrine neoplasia type 1 (MEN1) is a syndrome emerging from characteristic mutations of MEN1 gene with concurrently enunciated multiple endocrine and tumours and associated non-endocrine neoplasm. Previously designated as Werner’s syndrome, MEN1 syndrome denominates genomic mutation within chromosome 11q13 or a tumour suppressor gene with a distinctive protein product nomenclated as “menin”. MEN1 syndrome demonstrates an autosomal dominant pattern of disease inheritance where genomic mutations delineate a comprehensive (100%) disease penetrance. MEN1 gene was initially identified in 1997 upon chromosome 11q13. Although twelve genetic mutations were primarily identified, currently beyond eighteen hundred genomic mutations are scripted1, 2. MEN1 syndrome is comprised of diverse combination of twenty or more endocrine and non-endocrine tumours exemplifying a classic triad of pituitary, parathyroid and pancreatic neoplasm. Diverse non endocrine tumours enunciated with MEN1 syndrome are denominated with meningioma, ependymoma or angiofibroma1, 2. Endocrine tumours are discerned on account of excessive hormonal secretion engendered from various neoplasm or on account of neoplastic evolution. Approximately 10% instances can occur due to a de-novo genomic variant. Offspring of an individual with MEN1 syndrome quantifies a 50% possibility of inheriting the genomic variant. Cogent prenatal diagnosis can be determined in instances where specific genomic variant of a particular family is known. Physical, psychological and social restrictions are prevalent with MEN1 syndrome. Heterozygotes with MEN1 genetic variant are denominated as carriers and manifest a two- fold possible mortality1, 2.

Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease

BackgroundSensenbrenner syndrome, which is also known as cranioectodermal dysplasia (CED), is a rare, autosomal recessive ciliary chondrodysplasia characterized by a variety of clinical features including a distinctive craniofacial appearance as well as skeletal, ectodermal, liver and renal anomalies. Progressive renal disease can be life-threatening in this condition. CED is a genetically heterogeneous disorder. Currently, variants in any of six genes (IFT122, WDR35, IFT140, IFT43, IFT52 and WDR19) have been associated with this syndrome. All of these genes encode proteins essential for intraflagellar transport (IFT) a process that is required for cilium assembly, maintenance and function. Intra- and interfamilial clinical variability has been reported in CED, which is consistent with CED’s genetic heterogeneity and is indicative of genetic background effects.ResultsTwo male CED patients from two unrelated Polish families were included in this study. Clinical assessment revealed distinctive clinical features of Sensenbrenner syndrome, such as dolichocephaly, shortening of long bones and early onset renal failure. Ectodermal anomalies also included thin hair, short and thin nails, and small teeth in both patients. Next generation sequencing (NGS) techniques were performed in order to determine the underlying genetic cause of the disorder using whole exome sequencing (WES) for patient 1 and a custom NGS-based panel for patient 2. Subsequent qPCR and duplex PCR analysis were conducted for both patients. Genetic analyses identified compound heterozygous variants in the IFT140 gene in both affected individuals. Both patients harbored a tandem duplication variant p.Tyr1152_Thr1394dup on one allele. In addition, a novel missense variant, p.(Leu109Pro), and a previously described p.(Gly522Glu) variant were identified in the second allele in patients 1 and 2, respectively. Segregation analysis of the variants was consistent with the expected autosomal recessive disease inheritance pattern. Both patients had severe renal failure requiring kidney transplantation in early childhood.ConclusionThe finding of compound heterozygous IFT140 mutations in two unrelated CED patients provide further evidence that IFT140 gene mutations are associated with this syndrome. Our studies confirm that IFT140 changes in patients with CED are associated with early onset end-stage renal disease. Moreover, this report expands our knowledge of the clinical- and molecular genetics of Sensenbrenner syndrome and it highlights the importance of multidisciplinary approaches in the care of CED patients.

Assessing Knowledge of Sickle Cell Trait/Disease Inheritance in Metropolitan Detroit

Sickle cell disease (SCD) is an autosomal recessive disease not specific to one race. This study aims to assess knowledge about the inheritance pattern of sickle cell disease among college students in the Metropolitan Detroit area. An electronic survey was administered to undergraduate students at Oakland University, and first through fourth year medical students at Oakland University William Beaumont School of Medicine (OUWB). The primary analysis compared knowledge of sickle cell disease inheritance pattern between different demographic categories. A total of 146 Oakland University (27.4%) and OUWB (72.6%) students responded to the survey. The average age of the respondents was 24.27 ± 4.09. The majority of respondents were female (61%) and white (72.6%). In total, three (3) respondents - 1 white, 1 Asian and 1 African American, reported knowing that they have sickle cell disease/trait. In addition, one (1) white female respondent reported having an infant carrying the sickle cell trait. Most respondents (95.9%) knew that sickle cell disease/trait is genetically inherited, but a majority believed that it is associated only with African-Americans (67.8%). Respondents who were college graduates were more likely to correctly identify SCD inheritance patterns (98% compared to 85% of undergraduates; p = 0.002) and less likely to correctly answer the question “Who gets the disease?” (24% compared to 63%; p < 0.001). Most respondents (75%) think people should know if they have sickle cell trait/disease before marriage. The result shows that most respondents believe sickle cell disease is specific to African-Americans. However, because it is equally possible for all races to inherit this disease, knowing one's status could help prevent sickle cell-related deaths during rigorous exercises and enable individuals of reproductive age to make informed reproductive decisions in order to decrease sickle cell disease prevalence, and its associated financial and psychosocial burdens.

Whole genome sequencing and rare variant analysis in essential tremor families.

Essential tremor (ET) is one of the most common movement disorders. The etiology of ET remains largely unexplained. Whole genome sequencing (WGS) is likely to be of value in understanding a large proportion of ET with Mendelian and complex disease inheritance patterns. In ET families with Mendelian inheritance patterns, WGS may lead to gene identification where WES analysis failed to identify the causative single nucleotide variant (SNV) or indel due to incomplete coverage of the entire coding region of the genome, in addition to accurate detection of larger structural variants (SVs) and copy number variants (CNVs). Alternatively, in ET families with complex disease inheritance patterns with gene x gene and gene x environment interactions enrichment of functional rare coding and non-coding variants may explain the heritability of ET. We performed WGS in eight ET families (n = 40 individuals) enrolled in the Family Study of Essential Tremor. The analysis included filtering WGS data based on allele frequency in population databases, rare SNV and indel classification and association testing using the Mixed-Model Kernel Based Adaptive Cluster (MM-KBAC) test. A separate analysis of rare SV and CNVs segregating within ET families was also performed. Prioritization of candidate genes identified within families was performed using phenolyzer. WGS analysis identified candidate genes for ET in 5/8 (62.5%) of the families analyzed. WES analysis in a subset of these families in our previously published study failed to identify candidate genes. In one family, we identified a deleterious and damaging variant (c.1367G>A, p.(Arg456Gln)) in the candidate gene, CACNA1G, which encodes the pore forming subunit of T-type Ca(2+) channels, CaV3.1, and is expressed in various motor pathways and has been previously implicated in neuronal autorhythmicity and ET. Other candidate genes identified include SLIT3 which encodes an axon guidance molecule and in three families, phenolyzer prioritized genes that are associated with hereditary neuropathies (family A, KARS, family B, KIF5A and family F, NTRK1). Functional studies of CACNA1G and SLIT3 suggest a role for these genes in ET disease pathogenesis.

DNA Fingerprint Technology: Its Application in Detecting Pancreatic Cancer.

Pancreatic cancer (PC) is one of the most lethal forms of cancers, ranking as the third highest cause of malignancies and fatalities. Approximately 88% of patients diagnosed with PC are older than 55 yr. Due to PC's vague symptoms, patients typically visit their doctor only when they experience symptoms of extreme pain and/or after their bile ducts have blocked. This produces symptoms including darkly colored urine, jaundice, and light-colored stools. At this point in the progression of the disease, the tumor has already metastasized. Early detection of PC is critical and justifies the need for innovative techniques to efficiently aid in this process. Current research involves screening different aspects of the disease, imaging techniques, and evaluating blood, urine, cell, and saliva biomarkers. We propose that forensic DNA fingerprinting can be used to establish the role of genetics in PC, and we describe disease inheritance patterns so that relatives can understand the likelihood of developing this lethal malignancy.

Is routine genetic testing warranted in head and neck paragangliomas?

Is routine genetic testing warranted in head and neck paragangliomas?

Allogeneic Hematopoietic Stem Cell Transplantation in Children and Adults with Chronic Granulomatous Disease (CGD): A Study of the Inborn Errors Working Party (IEWP) of the EBMT

Introduction: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease characterized by impairment of the phagocyte NADPH-oxidase complex, resulting in deficient microbial killing and life-threatening bacterial and fungal infections. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative approach, but it can be complicated by graft failure, graft versus-host disease (GvHD) and transplant-related mortality (TRM). In order to define prognostic risk factors in this setting, the IEWP of the EBMT performed a large retrospective registry study on 600 pediatric and adult patients with CGD undergoing allo-HSCT.Patients and Methods: We analyzed the outcome of patients with CGD who received allo-HSCT in EBMT centers between 1993 and 2017. The main end-points of the study were overall survival (OS) and event-free survival (EFS; events were death and primary or secondary engraftment failure) according to patient's age, donor type, stem cell source and conditioning regimen. One patient died before allo-HSCT and was excluded from analysis.Results: We studied 536 children (aged < 18 years) and 63 adults (aged ≥ 18 years) affected by CGD. The median follow-up was 45.37 months (IQR 15.8-81.8). Genetic results were available for 307 patients: inheritance was X-linked (75%) or autosomal recessive (25%). Median age at transplant was 7.2 years (range: 0.12-48.56). Conditioning regimen was Busulfan/Fludarabine (n=244; 41%), Busulfan/Cyclophosphamide (n=104; 17%), Treosulfan/Fludarabine (n=76; 13%), Treosulfan/Fludarabine/Thiotepa (n=52; 9%) or other drug combinations (n=123; 20%). Donors were human leukocyte antigen (HLA) matched related (MFD, 10/10; n=211, 40%), matched unrelated (MUD, 10/10 or 6/6 in UCB; n=201; 38%), mismatched related (MMFD, ≥ 9/10; n= 27; 5%) or mismatched unrelated (MMUD, ≥ 9/10 or 5/6 in UCB; n= 83; 16%). Stem cell source was bone marrow (BM; n=408; 69%), peripheral blood (PB; n=153; 26%) or umbilical cord blood (UCB; n=27; 5%). Donor engraftment occurred in 516 evaluable patients (88%), while primary or secondary engraftment failure occurred in 68 patients (12%). Seventy-nine patients (13%) died after allo-HSCT.The 2 year Kaplan-Meier estimate of OS and EFS were 87.1% (95% CI, 84.2-89.9) and 77.8% (95% CI, 74.2-81.4), respectively (Fig A). The 2-year cumulative incidence of grade II-IV acute GvHD, chronic GvHD and extensive chronic GvHD was 18.6% (95%, 15.1-22.2), 16.2 % (95%, 18.8-19.7) and 5.5% (95%, 3.4-7.7), respectively. A univariate cox model with spline term demonstrated that older age at transplant was associated with an increased risk of death (p=0.002). Children undergoing allo-HSCT had a superior 2y OS (88.1%; 95% CI 85.2-91.0), compared to adults (78.2%; 95% CI, 67.7-88.7), p=0.03 (Fig B). Patients undergoing allo-HSCT from a MFD had a superior EFS (86.5%; 95% CI 81.5-91.4) compared to MUD (73.3%; 95% CI 66.7-79.9), MMUD (78.2%; 95% CI 69-87.5) and MMFD (59.7; 95% CI 40.4-79.1), p< 0.001 (Fig C). Patients receiving BM grafts had superior 2y EFS (81.0%; 95% CI 76.9-85.1) compared to PB (72.5%; 95% CI 64.7-80.4) and UCB (66.7%; 95% CI 48.9-84.4), p=0.04. The pattern of disease inheritance and the choice of conditioning regimen didn't have an impact on outcome (Fig D). Fifty-three patients with graft failure underwent a second allo-HSCT and the 2y OS in this group was 82.1% (95% CI, 71.5-92.7). Year of transplantation didn't have an influence on outcome.Conclusion: This is the largest study describing the outcome of allo-HSCT in children and adults affected by CGD. We demonstrate an excellent outcome, with a low incidence of graft failure, TRM and GvHD. Older patients with CGD have reduced survival after allo-HSCT, indicating that transplant should be considered at a younger age. The use of a MMFD is associated with poorer outcome; indication to transplant in this setting should be carefully evaluated by the treating physicians. DisclosuresChiesa:Bluebird Bio: Consultancy; Gilead: Consultancy. Kalwak:medac: Other: travel grants; Sanofi: Other: travel grants. Sykora:Aventis-Behring: Research Funding; medac: Research Funding. Locatelli:Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wynn:Orchard SAB: Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Equity Ownership; Chimerix: Research Funding; Genzyme: Honoraria; Bluebird Bio: Consultancy; Orchard Therapeutics: Consultancy; Chimerix: Consultancy. Zecca:Chimerix: Honoraria. Veys:Pfizer: Honoraria; Servier: Research Funding; Novartis: Honoraria. Slatter:Medac: Other: Travel assistance.

Homozygous alpha-synuclein p.A53V in familial Parkinson's disease

We have assessed the frequency of alpha-synuclein (SNCA) mutations in Japanese patients with familial or sporadic Parkinson's disease (PD) and surveyed their associated clinical manifestations. We screened SNCA exon 3 in 988 patients without SNCA multiplications (430 with autosomal dominant PD and 558 with sporadic PD). We detected 1 patient harboring a homozygous SNCA p.A53V substitution albeit with an autosomal dominant pattern of disease inheritance (frequency 2/860 = 0.2%). The proband manifested slow and progressive parkinsonism at 55 years. Later she complicated with cognitive decline and hallucinations. Several of her immediate family members also presented with parkinsonism, cognitive decline, and psychosis. Positron emission tomography imaging of 18F-6-fluoro-L-dopa (18F-DOPA) uptake, 11C(+)dihydrotetrabenzine (type 2 vesicular monoamine transporter), and 11C-d-threo-methylphenidate (a plasmalemmal dopamine transporter marker) binding in the striatum were significantly reduced. Hence, alpha-synuclein p.A53V homozygous mutation leads to a distinct phenotype of progressive parkinsonism and cognitive decline, commonly observed in patients with SNCA missense mutation or multiplications.

Identification of Novel Mutation in EIF2AK3 Gene as a Causal Variant in a Family With Rare Disease

Wolcott-Rallison syndrome (WRS) is now identified as the most frequent cause of neonatal/early onset diabetes in patients that initiated before 6 months of age. Inheritance pattern of disease is autosomal recessive and most of patients are from populations with frequent consanguineous marriages. WRS is caused by mutations in EIF2AK3 gene which encodes eukaryotic translation initiation factor 2a kinase. Several mutations have been reported in this gene and they are almost non-sense, frameshift, missense, and splice site. Here, we analyzed the EIF2AK3 gene in an Iranian girl suspicious for WRS. Sequencing analysis of the gene identified a homozygous novel non-sense mutation in exon 9 of the gene, Y479X. J Med Cases. 2017;8(3):102-104 doi: https://doi.org/10.14740/jmc2597e

Identification of Novel Mutation in EIF2AK3 Gene as a Causal Variant in a Family With Rare Disease

Wolcott-Rallison syndrome (WRS) is now identified as the most frequent cause of neonatal/early onset diabetes in patients that initiated before 6 months of age. Inheritance pattern of disease is autosomal recessive and most of patients are from populations with frequent consanguineous marriages. WRS is caused by mutations in EIF2AK3 gene which encodes eukaryotic translation initiation factor 2a kinase. Several mutations have been reported in this gene and they are almost non-sense, frameshift, missense, and splice site. Here, we analyzed the EIF2AK3 gene in an Iranian girl suspicious for WRS. Sequencing analysis of the gene identified a homozygous novel non-sense mutation in exon 9 of the gene, Y479X. J Med Cases. 2017;8(3):102-104 doi: https://doi.org/10.14740/jmc2597e