Unrelated Cases Research Articles

BBS1 branchpoint variant is associated with non-syndromic retinitis pigmentosa

BackgroundInherited retinal diseases (IRDs) can be caused by variants in >270 genes. The Bardet-Biedl syndrome 1 (BBS1) gene is one of these genes and may be associated with syndromic and...

UNC13B variants associated with partial epilepsy with favourable outcome.

The unc-13 homolog B (UNC13B) gene encodes a presynaptic protein, mammalian uncoordinated 13-2 (Munc13-2), which is highly expressed in the brain—predominantly in the cerebral cortex—and plays an essential role in synaptic vesicle priming and fusion, potentially affecting neuronal excitability. However, the functional significance of the UNC13B mutation in human disease is not known.In this study, we screened for novel genetic variants in a cohort of 446 unrelated cases (families) with partial epilepsy without acquired causes by trio-based whole-exome sequencing. UNC13B variants were identified in 12 individuals affected by partial epilepsy and/or febrile seizures from eight unrelated families. The eight probands all had focal seizures and focal discharges in EEG recordings, including two patients who experienced frequent daily seizures and one who showed abnormalities in the hippocampus by brain MRI; however, all of the patients showed a favourable outcome without intellectual or developmental abnormalities. The identified UNC13B variants included one nonsense variant, two variants at or around a splice site, one compound heterozygous missense variant and four missense variants that cosegregated in the families. The frequency of UNC13B variants identified in the present study was significantly higher than that in a control cohort of Han Chinese and controls of the East Asian and all populations in the Genome Aggregation Database (gnomAD). Computational modelling, including hydrogen bond and docking analyses, suggested that the variants lead to functional impairment. In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila. Electrophysiological recordings showed that excitatory neurons in Unc13b-deficient flies exhibited increased excitability.These results indicate that UNC13B is potentially associated with epilepsy. The frequent daily seizures and hippocampal abnormalities but ultimately favourable outcome under anti-epileptic therapy in our patients indicate that partial epilepsy caused by UNC13B variant is a clinically manageable condition.

Psychosis susceptibility zinc finger protein 804A (ZNF804A) gene polymorphism in schizophrenia patients treated with olanzapine in North Indian population

Purpose The Zinc finger protein 804A (ZNF804A) is a potential schizophrenia candidate gene that has emerged from genome-wide association studies. The aim of the study is to investigate whether this gene variant influences the response of positive or negative symptoms to antipsychotic drug olanzapine in North Indian schizophrenia patients. Materials and methods Our study involved 184 unrelated schizophrenia cases (114 males and 70 females; mean age: 52.8 ± 11.6 years) and 300 normal controls (168 males and 132 females; mean age: 54.9 ± 6.9 years). At the start of treatment and after four weeks, we assessed the response of positive and negative symptoms by positive and negative syndrome scale (PANSS). Olanzapine drug level was estimated using HPLC Method and Genotyping was performed using PCR-Snap Shot technique. Results Significant differences were observed in the genotype distribution (χ 2 = 6.10, d.f. = 2, p = 0.04) and allele frequencies (χ 2 = 5.14, d.f. = 1, p = 0.02; odds ratio = 0.57, 95% confidence interval =1.09–3.48) between schizophrenia patients and controls group. The improvement of positive and negative schizophrenia symptoms after 4 weeks of treatment with olanzapine was assessed. Patients homozygous for the ZNF804A risk allele for AA show poorer improvement of positive symptoms compared to patients with a protective allele. Conclusions Our findings indicate that ZNF804A gene polymorphism plays a significant role in the treatment of schizophrenia, suggesting that ZNF804A may be an effective marker for schizophrenia treatment.

A glimpse of the genetics of young-onset Parkinson's disease in Central Asia.

ABSTRACTBackgroundKnowledge of the genetic background of many human diseases is currently lacking from genetically undiscovered regions, including Central Asia. Kazakhstan is the first Central Asian country where the genetic studies of Parkinson's disease (PD) have been emerging since it had become a member of the International Parkinson Disease Genomics Consortium. Here we report on the results of whole‐exome sequencing (WES) in 50 young‐onset PD (YOPD) cases from Kazakhstan.MethodologyWES was performed on 50 unrelated individuals with YOPD from Kazakhstan. Exome data were screened for novel/ultra‐rare deleterious variants in known and candidate PD genes. Copy number variants and small indels were also called.ResultsOnly three cases (6%) were found to be positive for known PD genes including two unrelated familial PD cases with LRRK2 p.(Arg1441Cys) and one case with a homozygous pathogenic PRKN p.(Arg84Trp) variant. Four cases had novel and ultra‐rare variants of uncertain significance in LRRK2, DNAJC13, and VPS35. Novel deleterious variants were found in candidate Mendelian PD genes including CSMD1, TNR, EIF4G1, and ATP13A3. Eight cases harbored the East Asian‐specific LRRK2 p.(Ala419Val) variant.ConclusionsThe low diagnostic yield in our study might imply that a significant proportion of YOPD cases in Central Asia remains unresolved. Therefore, a better understanding of the genetic architecture of PD among populations of Central Asian ancestry and the pathogenicity of numerous rare variants should be further investigated. WES is a valuable technique for large‐scale YOPD genetic studies in Central Asia.

Upper mini sternotomy approach for pulmonary artery banding: A single centre experience.

Pulmonary artery banding (PAB) remains a crucial technique in modern cardiac surgery. Left lateral thoracotomy, median sternotomy, and left anterior thoracotomy are well-known approaches. With significant scarce reports addressing the application of the upper mini sternotomy approach for PAB, this study aims to share experience and report outcomes of patients operated upon using this approach and its impact on facilitating the redo surgery. Since 2015, we practiced the use upper mini sternotomy approach for PAB in the study center where we conducted this retrospective study of 22 patients who underwent banding through the upper mini sternotomy approach. Indications varied between complete atrioventricular septal defect, multiple muscular ventricular septal defects, and univentricular heart with increased pulmonary blood flow. At the time of PAB, the medians of age 2.0 (1-4.5) months and bodyweight of 3.1 (1.9-4.2) kg were reported against a surgery time range of 75- 135 min and peak gradient across the band of 54-78 mmHg. There was one unrelated mortality case (4.5%) due to a severe attack of pulmonary hypertensive crisis. Fifteen patients underwent the redo surgery. No mortality or sternotomy-related complications were reported following the second stage surgery while the reopening time ranged between 17 and 32 min. The upper mini sternotomy approach for PAB is safe and facilitates the subsequent redo surgery and could be a valuable alternative to other surgical approaches.

EP022 - Two unrelated cases of mild methylmalonic acidemia-mutase deficiency with shared variant treated with vitamin B12 only

eP022 - Two unrelated cases of mild methylmalonic acidemia-mutase deficiency with shared variant treated with vitamin B12 only

PLASMA N-GLYCOME AS INCIDENCE HYPERTENSION PREDICTOR

Objective: N-glycosylation, one of the most complex co- and post-translational modifications, is a highly regulated process influenced by many diseases. There is evidence that N-glycosylation could be a marker of hypertension. The aim of this study was to determine if plasma N-glycome is predictor of incident hypertension (HTN). Design and method: We selected 271 unrelated cases with incident hypertension and 271 controls matched for age, BMI and follow-up time from the TwinsUK cohort (mean follow-up time was 8.5 years). Longitudinal plasma N-glycome (39 directly measured traits) was measured by ultra-performance liquid chromatography (HILIC-UPLC). Logistic regression with elastic net penalty (a = 1 and l = 10e-2) and 10-fold cross validation was implemented on this subset fitting two models: null, with baseline age, BMI and follow-up time, and glyco, with null + baseline plasma N-glycans as predictors. Models were evaluated by comparing their area under the curves using bootstrap test. Most important glycans contributing to prediction of incident HTN in elastic net were further assessed by Cox survival analysis to estimate their effect on the risk of incident HTN. Cox models were fitted using the whole dataset, with baseline BMI and age as covariates and Family ID as random effect. Results: Glyco model (AUC = 0.628, 95%CI = 0.582–0.675) was significantly better in prediction of incident HTN in contrast to null model (AUC = 0.524, 95%CI = 0.475–0.570; p < 0.001) explaining an extra 10%. The glyco model identified 6 plasma glycans mostly contributing to the prediction. These include four high branched structures with two to four sialic acids (GP25, GP27, GP31, GP32) originating from a-1-acid glycoprotein, one structure with two branches and one sialic acid (GP15), and one glycan peak (GP2) without sialic acid, related to high mannose structure or structure ending with a bisecting N-acetylglucosamine residue. Cox survival analysis showed that only GP32 significantly increased risk (log(HR) = 0.253, 95%CI = 0.075–0.432; p = 0.006) of incident hypertension. Conclusions: Baseline plasma N-glycome is associated with incident hypertension in our cohort of adult female subjects. N-glycome of a-1-acid glycoprotein appears to contribute the most to hypertension risk and merits further validation studies in independent cohorts.

Hunting for Familial Parkinson's Disease Mutations in the Post Genome Era.

Parkinson’s disease (PD) is typically sporadic; however, multi-incident families provide a powerful platform to discover novel genetic forms of disease. Their identification supports deciphering molecular processes leading to disease and may inform of new therapeutic targets. The LRRK2 p.G2019S mutation causes PD in 42.5–68% of carriers by the age of 80 years. We hypothesise similarly intermediately penetrant mutations may present in multi-incident families with a generally strong family history of disease. We have analysed six multiplex families for missense variants using whole exome sequencing to find 32 rare heterozygous mutations shared amongst affected members. Included in these mutations was the KCNJ15 p.R28C variant, identified in five affected members of the same family, two elderly unaffected members of the same family, and two unrelated PD cases. Additionally, the SIPA1L1 p.R236Q variant was identified in three related affected members and an unrelated familial case. While the evidence presented here is not sufficient to assign causality to these rare variants, it does provide novel candidates for hypothesis testing in other modestly sized families with a strong family history. Future analysis will include characterisation of functional consequences and assessment of carriers in other familial cases.

Molecular Spectrum of β-Thalassemia Mutations in Central to Eastern Thailand

The aim of this study was to determine the molecular spectrum of β-thalassemia (β-thal) mutations in eastern Thailand. We identified β-thal mutations using allele specific-polymerase chain reaction (ASPCR) and direct DNA sequencing. We found 18 different β-thal mutations in a total of 191 unrelated subjects. Six common β-thal mutations comprised 86.91% of all the mutations, including codons 41/42 (–TTCT) (HBB: c.126_129delCTTT) (35.60%), codon 17 (A>T) (HBB: c.52A>T) (18.85%), −28 (A>G) (HBB: c.-78A>G) (15.71%), IVS-II-654 (C>T) (HBB: c.316-197C>T) (6.28%), IVS-I-1 (G>T) (HBB: c.92+1G>T) (5.76%) and codon 19 (A>G) (HBB:(c.59A>G) (4.71%). In addition, a novel 60 kb deletion in two unrelated cases was characterized and initially suspected to originate from eastern Thailand. Moreover, we demonstrated the molecular spectrum of recent β-thal mutations in Thailand, and data from this study were compared with five reference laboratory centers in Thailand. This study is the first to identify the comprehensive molecular spectrum of β-thal mutations in eastern Thailand, information that may be essential for screening, genetic counseling and prenatal diagnosis (PND) in this region.

Interaction of IL-6 gene with tumor necrosis factor-α and white blood cell in metabolic syndrome

To investigate the associations between the polymorphisms and interaction of the interleukin 6(IL-6) genes at-634 C/G, -174 G/C, -1363 G/T loci, as well as the interactions between the three loci and tumor necrosis factor(TNF-α), and peripheral blood leukocytes(white blood cell, WBC) with metabolic syndrome(MS). Using the case-control research method, according to the inclusion and exclusion criteria, from March 2015 to March 2016 from the General Hospital of Ningxia Medical University and Wuzhong City People's Hospital, 376 unrelated cases and 408 control groups were selected. We conducted questionnaire surveys(including general conditions, disease and medication history, family history, etc. ), physical examinations(including height, weight and calculation of body mass index(BMI), waist circumference, hip circumference and calculation of waist-to-hip ratio(WHR), SBP, DBP, etc. ), blood collection and testing(including WBC count, serum TNF-α level and biochemical indicators TG, TC, HDL-C, LDL-C, FPG, UA, AST, ALT, etc. ), and the polymorphism detection of IL-6 gene at-634 C/G, -174 G/C, -1363 G/T sites. The SNPstats online software was used to analyze the relationship between the polymorphisms of IL-6 gene and MS. The SHEsis online software was used to analyze the linkage disequilibrium(LD) of the IL-6 three-site and the relationship between haplotype and MS. GMDR 0. 7 software was used to analyze the interactions among the three sites of IL-6 gene, and one between the three sites and TNF-α and WBC, respectively. Before and after adjustment of sex, age and nationality, the polymorphism at the 3 position of IL-6 gene was not related to the onset of MS in different genetic models(both P> 0. 05). There was a linkage disequilibrium between the three loci of IL-6 gene, but the haploids formed by these three loci were not associated with MS susceptibility(all P> 0. 05). There was no interaction among the three sites, but the two-factor, three-factor, and four-factor interaction models consisting of the three sites and TNF-α were all statistically significant(all P<0. 001) and the replacement tests were all P<0. 001, and were all associated with MS occurrence. The two-factor, three-factor, and four-factor interaction models consisting of the three sites and WBC were all P<0. 01, and the replacement tests were all P<0. 05. The differences were statistically significant, which was related to the onset of MS. The IL-6 gene-634 C/G, -174 G/C, and-1363 G/T loci polymorphism may not be significantly associated with the prevalence of MS. Interactions between the three sites and TNF-α and WBC levels can significantly increase the risk of MS.

Identification of OPN3 as associated with non-syndromic oligodontia in a Japanese population.

Tooth agenesis is one of the most frequent congenital abnormalities found in the maxillofacial region. Oligodontia, a severe form of tooth agenesis, occurs as an isolated anomaly or as a syndromic feature. We performed whole exome sequencing analyses to identify causative mutation in a Japanese family with three affected individuals with non-syndromic oligodontia. After variant filtering procedures and validation by Sanger sequencing, we identified one missense mutation (c.668 C > T, p.Gly223Asp) in OPN3 at 1q43, encoding a photosensitive G-protein-coupled receptor (GPCR) expressed in various tissues including brain, liver, and adipose. This mutation was predicted to be pathogenic in silico and was not found in the public databases. We further examined 48 genetically unrelated cases by targeted sequencing of the OPN3 gene region and found one additional missense variant in this gene (c.768 C > T, p.Met256Ile) that was also predicted to be pathogenic. Localization of OPN3 protein by immunohistochemical analysis using mouse embryo revealed its specific expression in the tooth gems from bud to bell stages and their surrounding tissues. These results indicated that OPN3 was involved in non-syndromic oligodontia, which has made an anchoring point for clinical application including DNA diagnostics.

Autosomal dominant familial acanthosis nigricans caused by a C-terminal nonsense mutation of FGFR3

FGFR3 encodes a transmembrane receptor tyrosine kinase that has six autophosphorylation sites of tyrosine. Among them, Y770 is a negative regulatory site for the downstream signaling of FGFR3. Constitutive active mutations in FGFR3 are involved in human developmental disorders including familial acanthosis nigricans, an autosomal dominant disorder characterized by general hyperpigmentation with mild acanthosis of the epidermis. Here, we report two unrelated cases of familial acanthosis nigricans with a heterozygous c.2302G>T (p.E768*) mutation in FGFR3 (NM_000142.5). FGFR3 mRNA purified from the skin lesion neither showed aberrant splicing nor nonsense-mediated mRNA decay, indicating that the FGFR3 mutant simply lacked the C-terminal 768-806 amino acids including Y770. While all of the known pathogenic mutations were missense mutations in FGFR3 showing autosomal dominant trait, the c.2302G>T mutation of FGFR3 is a unique autosomal dominant nonsense mutation that causes familial acanthosis nigricans probably via loss of negative regulatory autophosphorylation site of FGFR3.

Usefulness of NGS for Diagnosis of Dominant Beta-Thalassemia and Unstable Hemoglobinopathies in Five Clinical Cases.

Unstable hemoglobinopathies (UHs) are rare anemia disorders (RADs) characterized by abnormal hemoglobin (Hb) variants with decreased stability. UHs are therefore easily precipitating, causing hemolysis and, in some cases, leading to dominant beta-thalassemia (dBTHAL). The clinical picture of UHs is highly heterogeneous, inheritance pattern is dominant, instead of recessive as in more prevalent major Hb syndromes, and may occur de novo. Most cases of UHs are not detected by conventional testing, therefore diagnosis requires a high index of suspicion of the treating physician. Here, we highlight the importance of next generation sequencing (NGS) methodologies for the diagnosis of patients with dBTHAL and other less severe UH variants. We present five unrelated clinical cases referred with chronic hemolytic anemia, three of them with severe blood transfusion dependent anemia. Targeted NGS analysis was performed in three cases while whole exome sequencing (WES) analysis was performed in two cases. Five different UH variants were identified correlating with patients’ clinical manifestations. Four variants were related to the beta-globin gene (Hb Bristol—Alesha, Hb Debrousse, Hb Zunyi, and the novel Hb Mokum) meanwhile one case was caused by a mutation in the alpha-globin gene leading to Hb Evans. Inclusion of alpha and beta-globin genes in routine NGS approaches for RADs has to be considered to improve diagnosis’ efficiency of RAD due to UHs. Reducing misdiagnoses and underdiagnoses of UH variants, especially of the severe forms leading to dBTHAL would also facilitate the early start of intensive or curative treatments for these patients.

A high frequency and geographical distribution of MMACHC R132* mutation in children with cobalamin C defect.

Cobalamin C defect is caused by pathogenic variants inthe MMACHCgene leading to impaired conversion of dietary vitamin B12into methylcobalamin and adenosylcobalamin. Variants inthe MMACHCgene cause accumulation of methylmalonic acid and homocysteine along with decreased methionine synthesis. The spectrum of MMACHC gene variants differs in various populations. A total of 19 North Indian children (age 0-18years) with elevated methylmalonic acid and homocysteine were included in the study, and their DNA samples were subjected to Sanger sequencing of coding exons with flanking intronic regions of MMACHC gene. The genetic analysis resulted in the identification of a common pathogenic nonsense mutation, c.394C > T (R132*) in 85.7% of the unrelated cases with suspected cobalamin C defect. Two other known mutations c.347T > C (7%) and c.316G > A were also detected. Plasma homocysteine was significantly elevated (> 100µmol/L) in 75% of the cases and methionine was decreased in 81% of the cases. Propionyl (C3)-carnitine, the primary marker for cobalamin C defect, was found to be elevated in only 43.75% of cases. However, the secondary markers such as C3/C2 and C3/C16 ratios were elevated in 87.5% and 100% of the cases, respectively. Neurological manifestations were the most common in our cohort. Our findings of the high frequency of a single MMACHC R132* mutation in cases with combined homocystinuria and methylmalonic aciduria may be proven helpful in designing a cost-effective and time-saving diagnostic strategy for resource-constraint settings. Since the R132* mutation is located near the last exon-exon junction, this is a potential target for the read-through therapeutics.

Evaluation of microhaplotypes in forensic kinship analysis from a Swedish population perspective

The development of massively parallel sequencing (MPS) technology has enabled the discovery of several new types of forensic markers where microhaplotypes are one of these promising novel genetic markers. Microhaplotypes are, commonly, less than 300 nucleotides in length and consist of two or more closely linked single-nucleotide polymorphisms (SNPs). In this study, we have examined a custom-made QIAseq Microhaplotype panel (Qiagen), including 45 different microhaplotype loci. DNA libraries were prepared according to the GeneRead DNAseq Targeted Panels V2 library preparation workflow (Qiagen) and sequenced on a MiSeq FGx instrument (Verogen). We evaluated the performance of the panel based on 75 samples of Swedish origin and haplotype frequencies were established. We performed sensitivity studies and could detect haplotypes at input amounts down to 0.8 ng. We also studied mixture samples with two contributors for which haplotypes, for the minor contributor, were detectable down to the level of 1:100. Furthermore, we executed kinship simulations to evaluate the usefulness of this panel in kinship analysis. The results showed that both paternity and full sibling cases can clearly be solved. When simulating a half sibling versus unrelated case scenario, there were, however, some overlap of the likelihood ratio distributions potentially resulting in inconclusiveness. To conclude, the results of this initial study are promising for further implementation of this microhaplotype assay into the forensic field, although we noticed some primer design issues that could be optimized, which possibly would increase the power of the assay.

Clinical and Genetic Profile of X-Linked Agammaglobulinemia: A Multicenter Experience From India.

BackgroundThere is paucity of literature on XLA from developing countries. Herein we report the clinical and molecular profile and outcome in a multicenter cohort of patients with XLA from India.MethodsData on XLA from all regional centers supported by the Foundation for Primary Immunodeficiency Diseases (FPID), USA and other institutions providing care to patients with PIDs were collated. Diagnosis of XLA was based on European Society for Immunodeficiencies (ESID) criteria.ResultsWe received clinical details of 195 patients with a provisional diagnosis of XLA from 12 centers. At final analysis, 145 patients were included (137 ‘definite XLA’ and eight ‘probable/possible XLA’). Median age at onset of symptoms was 12.0 (6.0, 36.0) months and median age at diagnosis was 60.0 (31.5, 108) months. Pneumonia was the commonest clinical manifestation (82.6%) followed by otitis media (50%) and diarrhea (42%). Arthritis was seen in 26% patients while 23% patients developed meningitis. Bronchiectasis was seen in 10% and encephalitis (likely viral) in 4.8% patients. Pseudomonas aeruginosa was the commonest bacterial pathogen identified followed by Streptococcus pneumoniae, Staphylococcus aureus and Klebsiella pneumoniae. Molecular analysis revealed 86 variants in 105 unrelated cases. Missense variants in BTK gene were the most common (36%) followed by frameshift (22%) and nonsense variants (21%). Most pathogenic gene variants (53%) were clustered in the distal part of gene encompassing exons 14–19 encoding for the tyrosine kinase domain. Follow-up details were available for 108 patients. Of these, 12% had died till the time of this analysis. The 5-year and 10-year survival was 89.9% and 86.9% respectively. Median duration of follow-up was 61 months and total duration of follow-up was 6083.2 patient-months. All patients received intravenous immunoglobulin (IVIg) replacement therapy. However, in many patients IVIg could not be given at recommended doses or intervals due to difficulties in accessing this therapy because of financial reasons and lack of universal health insurance in India. Hematopoietic stem cell transplant was carried out in four (2.8%) patients.ConclusionThere was a significant delay in the diagnosis and facilities for molecular diagnosis were not available at many centers. Optimal immunoglobulin replacement is still a challenge

Association of a novel PKHD1 mutation in a family with autosomal dominant polycystic liver disease.

BackgroundAutosomal dominant polycystic liver disease (ADPLD) is characterized by multiple cysts in the liver without (or only occasional) renal cysts. At least seven genes are associated with high risk for developing ADPLD; however, clear genetic involvement is undetermined in more than 50% of ADPLD patients.MethodsTo identify additional ADPLD-associated genes, we collected 18 unrelated Chinese ADPLD cases, and performed whole exome sequencing on all the participants. After filtering the sequencing data against the human gene mutation database (HGMD) professional edition, we identified new mutations. We then sequenced this gene in family members of the patient.ResultsAmong the 18 ADPLD cases analyzed by whole exome sequencing, we found 2 cases with a PRKCSH mutation (~11.1%), 2 cases with a PKD2 mutation (~11.1%), 1 case with both PKHD1 and PKD1 mutations (~5.6%), 1 case with GANAB mutation (~5.6%), 1 case with PKHD1 mutation (~5.6%), and 1 case with PKD1 mutations (~5.6%). We identified a new PKHD1 missense mutation in an ADPLD family, in which both patients showed innumerable small hepatic cysts, as reported previously. Additionally, we found that PRKCSH and SEC63 mutation frequencies were lower in the Chinese population compared with those in European and American populations.ConclusionsWe report a family with ADPLD associated with a novel PKHD1 mutation (G1210R). The genetic profile of ADPLD in the Chinese population is different from that in European and American populations, suggesting that further genetic research on genetic mutation of ADPLD in the Chinese population is warranted.

Urinary Bladder Inflammatory Myofibroblastic Tumor With Mutated TP53 and PPFIBP1-ALK Gene Fusion

Abstract Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm with distinct histologic features. Approximately 50% of these tumors harbor ALK gene rearrangements with multiple gene fusion partners described, a few of which are predictive of poor prognosis. One example is the ALK-RANBP2 gene rearrangement identified in cases of epithelioid myofibroblastic sarcomas. Many studies have attempted to identify other immunohistochemical or molecular features, which may be predictive of outcome, with conflicting results, particularly regarding the expression of p53. In addition, aberrant p53 expression may be used to favor a diagnosis of leiomyosarcoma over IMT. We present the case of a deeply invasive urinary bladder IMT with aberrant p53 expression and corresponding TP53 genomic alteration, the latter previously reported in only 2 unrelated cases of malignancy. Our case highlights that p53 aberrant expression and TP53 genomic alterations may be found in IMTs and may be related to IMT pathogenesis and prognosis. Furthermore, relying on absence of aberrant p53 expression in IMT in order to distinguish it from histologic mimickers may lead to potential diagnostic pitfalls. In addition, our case demonstrated weak immunohistochemical staining for ALK and was found to harbor a PPFIBP1-ALK gene fusion, previously described in only 2 reports of IMTs of the lung, also with associated negative or weak immunohistochemical staining for ALK.

Epilepsy with auditory features: Contribution of known genes in 112 patients

Epilepsy with Auditory Features (EAF) is a focal epilepsy syndrome mainly of unknown aetiology. LGI1 and RELN have been identified as the main cause of Autosomal Dominant EAF and anecdotally reported in non-familial cases. Pathogenic variants in SCN1A and DEPDC5 have also been described in a few EAF probands belonging to families with heterogeneous phenotypes and incomplete penetrance. We aimed to estimate the contribution of these genes to the disorder by evaluating the largest cohort of EAF. We included 112 unrelated EAF cases (male/female: 52/60) who underwent genetic analysis by next-generation sequencing (NGS) techniques. Thirty-three (29.5%) were familial cases. We identified a genetic diagnosis for 8% of our cohort, including pathogenic/likely pathogenic variants (4/8 novel) in LGI1 (2.7%, CI: 0.6-7.6); RELN (1.8%; CI: 0.2-6.3); SCN1A (2.7%; CI: 0.6-7.6) and DEPDC5 (0.9%; CI 0-4.9).This study shows that the contribution of each of the known genes to the overall disorder is limited and that the genetic background of EAF is still largely unknown. Our data emphasize the genetic heterogeneity of EAF and will inform the diagnosis and management of individuals with this disorder.

Clinical and molecular characteristics of Thai patients with ELANE-related neutropaenia

AimsCongenital neutropaenia is a rare inherited disorder that mainly affects neutrophils causing severe infection. Mutations in several genes have been implicated in the disease pathogenesis. The genetic defects may vary...