An investigation of the etiology and follow-up findings in 35 children with overgrowth syndromes, including biallelic SUZ12 variant.

Overgrowth-intellectual disability (OGID) syndromes are clinically and genetically heterogeneous group of disorders. The aim of this study was to examine the molecular etiology and long-term follow-up findings of Turkish OGID cohort. Thirty-five children with OGID were included in the study. Single gene sequencing, clinical exome analysis, chromosomal microarray analysis and whole exome sequencing were performed. Five pathogenic copy number variants were detected in the patients; three of them located on chromosome 5q35.2 (encompassing NSD1), others on 9q22.3 and 22q13.31. In 19 of 35 patients; we identified pathogenic variants in OGID genes associated with epigenetic regulation, NSD1 (n = 15), HIST1H1E (n = 1), SETD1B (n = 1), and SUZ12 (n = 2). The pathogenic variants in PIK3CA (n = 2), ABCC9 (n = 1), GPC4 (n = 2), FIBP (n = 1), and TMEM94 (n = 1) which had a role in other growth pathways were detected in seven patients. The diagnostic yield was 31/35(88%). Twelve pathogenic variants were novel. The common facial feature of the patients was prominent forehead. The patients with Sotos syndrome were observed to have milder intellectual disability than patients with other OGID syndromes. In conclusion, this study showed, for the first time, that biallelic variants of SUZ12 caused Imagawa-Matsumoto syndrome, monoallelic variants in SETDIB resulted in OGID. Besides expanded the phenotypes of very rare OGID syndromes caused by FIBP and TMEM94.

Biallelic variants in ADAMTS15 cause a novel form of distal arthrogryposis.

PURPOSE: We aimed to identify the underlying genetic cause for a novel form of distal arthrogryposis. METHODS: Rare variant family-based genomics, exome sequencing, and disease-specific panel sequencing were used to detect ADAMTS15 variants in affected individuals. Adamts15 expression was analyzed at the single-cell level during murine embryogenesis. Expression patterns were characterized using in situ hybridization and RNAscope. RESULTS: We identified homozygous rare variant alleles of ADAMTS15 in 5 affected individuals from 4 unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. Radiographic investigations showed physiological interphalangeal joint morphology. Additional features included knee, Achilles tendon, and toe contractures, spinal stiffness, scoliosis, and orthodontic abnormalities. Analysis of mouse whole-embryo single-cell sequencing data revealed a tightly regulated Adamts15 expression in the limb mesenchyme between embryonic stages E11.5 and E15.0. A perimuscular and peritendinous expression was evident in in situ hybridization in the developing mouse limb. In accordance, RNAscope analysis detected a significant coexpression with Osr1, but not with markers for skeletal muscle or joint formation. CONCLUSION: In aggregate, our findings provide evidence that rare biallelic recessive trait variants in ADAMTS15 cause a novel autosomal recessive connective tissue disorder, resulting in a distal arthrogryposis syndrome.

Specific early signs and long-term follow-up findings of progressive pseudorheumatoid dysplasia (PPRD) in the Turkish cohort.

OBJECTIVES: Progressive pseudorheumatoid dysplasia (PPRD) is a spondyloepiphyseal dysplasia caused by biallelic variants in CCN6. This study aimed to describe the early signs and follow-up findings in 44 Turkish PPRD patients. METHODS: The patients with progressive stiffness of multiple joints, characteristic wide metaphysis of interphalangeal (IP) joints and platyspondyly were clinically diagnosed with PPRD. Fifteen patients who had first symptoms under 3 years of age were grouped as early-onset, while others were grouped as classical. CCN6 sequencing was performed in 43 patients. RESULTS: Thirteen pathogenic/likely pathogenic variants were identified, five were novel. c.156C>A(p.Cys52*) variant was found in 53.3% of the families. The initial symptom in the early-onset group was genu varum deformity, while it was widening of IP joints in the classical group. The median age of onset of symptoms and of diagnosis was 4 and 9.7 years, respectively. The mean follow-up duration was 5.6 years. The median age of onset of IP, elbow, knee and hip stiffness, which became progressive with growth was 5, 9, 9 and 12.2 years, respectively. Waddling gait occurred in 97.7% of the patients. A total of 47.7% lost independent walking ability at the median age of 12 years. In the early-onset group, waddling gait occurred earlier than in classical group (P < 0.001). Two patients had atypical presentation with late-onset and mild or lack of IP involvement. CONCLUSION: We observed that genu varum deformity before the age of 3 years was an early sign for PPRD and almost half of the patients lost walking ability at the median age of 12 years.

Severe combined immunodeficiencies: Expanding the mutation spectrum in Turkey and identification of 12 novel variants.

Human Inborn Errors of Immunity (IEIs) are clinically and genetically heterogeneous group of diseases, with relatively mild clinical course or severe types that can be life-threatening. Severe combined immunodeficiency (SCID) is the most severe form of IEIs, which is caused by monogenic defects that impair the proliferation and function of T, B, and NK cells. According to the most recent report by the International Union of Immunological Societies (IUIS), SCID is caused by mutations in IL2RG, JAK3, FOXN1, CORO1A, PTPRC, CD3D, CD3E, CD247, ADA, AK2, NHEJ1, LIG4, PRKDC, DCLRE1C, RAG1 and RAG2 genes. The targeted next-generation sequencing (TNGS) workflow based on Ion AmpliSeq™ Primary Immune Deficiency Research Panel was designed for sequencing 264 IEI-related genes on Ion S5™ Sequencer. Herein, we present 21 disease-causing variants (12 novel) which were identified in 22 patients in eight different SCID genes. Next-generation sequencing allowed a rapid and an accurate diagnosis SCID patients.

A Novel Homozygous TRNT1 Mutation in a Child With an Early Diagnosis of Common Variable Immunodeficiency Leading to Mild Hypogammaglobulinemia and Hemolytic Anemia.

Although sideroblastic anemias (SAs) may be associated with different etiologies, deterioration of mitochondrial heme biosynthesis in bone marrow erythroid cells is a general abnormality. Congenital SA associated with immunodeficiency, periodic fever, and developmental delay is because of loss-of-function mutations in the TRNT1 gene. We report a patient with a novel homozygous mutation in the TRNT1 gene presenting with anemia with siderocytes, hypogammaglobulinemia, hepatosplenomegaly, and brittle hair but without periodic fever or developmental delay. The patient was presented to emphasize the power of reverse phenotyping in the differential diagnosis of primary immunodeficiency patients with atypical features and to raise awareness for TRNT1 disease in case of coexistent SA and hypogammaglobulinemia.

Combined immunodeficiency with marginal zone lymphoma due to a novel homozygous mutation in IL-21R gene and successful treatment with hematopoietic stem cell transplantation.

Mutations in the interleukin-21 receptor (IL-21R) gene are recently defined as primary immunodeficiency diseases. IL-21R defects result in combined immunodeficiency by affecting the functions of innate and adaptive immune system components.A six-year-old girl was admitted to our hospital with complaints of chronic diarrhea that started after the newborn period and generalized rash over the last three months. She had severe respiratory distress due to Cytomegalovirus (CMV) pneumonia requiring mechanical ventilation and was diagnosed as combined immunodeficiency at another hospital at the age of four. Her physical examination on admission revealed erythematous rash on cheeks, extremities, gluteal region, and lymph node enlargements in cervical, axillary, and inguinal regions. CMV DNA and stool Cryptosporidium parvum were positive. Marginal zone lymphoma -negative for Epstein-Bar virus- was reported in the lymph node biopsy. Targeted next-generation sequencing Ion AmpliSeq™ primary immunodeficiency panel revealed a novel homozygous IL21R c.132delC (p.Ser45fs) mutation.This case is presented to emphasize that IL21R defects should be considered in the differential diagnosis of the patients with recurrent respiratory infections, chronic diarrhea, C. parvum infection, chronic liver disease, sclerosing cholangitis, and malignancy where early hematopoietic stem cell transplantation (HSCT) is life-saving. A total of eight cases with IL21R gene defects have been reported so far. The significance of this case is that it is the first case of malignancy among the published IL-21R deficient patients successfully treated with HSCT.

20-year experience on prenatal diagnosis in a reference university medical genetics center in Turkey

Background/aim: Although cutting edge procedures such as cell-free fetal DNA isolation from maternal blood are now available, invasive prenatal tests are still being used extensively for prenatal diagnosis. The study aims to evaluate the demographic data, indications, and cytogenetic results of 9297 results of patients who underwent prenatal invasive testing for genetic analysis that were referred for the last 20 years in a University Medical Genetics Center. Materials and methods: The records of 8363 amniocenteses, 626 chorionic villus, and 308 cordocenteses samples were retrospectively evaluated and analyzed regarding referral reasons, indications and their cytogenetic results. The total numbers and the percentages of each group were recorded; Chi-square and logistic regression analyses were performed to give the statistical likelihood of different events. Results: The number of referrals decreased significantly after 2009. Risk of having trisomy 21 as well as trisomy 13 and 18 significantly increased in parallel with advanced maternal age. When the 21­25 age group was compared to the older age groups in terms of having a trisomy 21 pregnancy, the risk doubled in the 36­40, 5 times higher in 41­45 and 10-fold in 46­50 age groups. No significant linear correlation between maternal serum screening test results and trisomy 21 was found, however the difference between the pregnancies whom cut-off value above and below 1/250 in maternal serum screening test were significant. Conclusion: These data have provided useful information on the frequency of referrals to the reference genetics department, and the feasibility of genetic services. By reviewing the indications and their corresponding results, we can offer invaluable insights that will be useful in genetic counseling and also in the development of more effective genetic strategies.

Clinical and molecular aspects of PTEN mutations in 10 pediatric patients.

INTRODUCTION: PTEN gene mutations are responsible for the PTEN hamartoma tumor syndrome (PHTS). In this study, clinical and molecular findings of patients carrying PTEN mutations are presented. Our aim is to contribute to genotype-phenotype correlation and define the most common findings of the syndrome in pediatric patients. METHODS AND MATERIALS: Ten molecularly confirmed PHTS patients from seven families were included in the study. All patients were examined by a clinical geneticist. Laboratory test results were obtained from hospital records. Sequencing of PTEN gene was performed. Variant interpretation was done in accordance with 2015 recommendations from the American College of Medical Genetics. RESULTS: Macrocephaly was the most common clinical finding, involving all patients. This was followed by skin lesions, neurodevelopmental delay, and pathologic cranial magnetic resonance imaging findings. Seven different heterozygous PTEN gene variants were found in seven families. Four of these were located in exon 5, which has been described as a hot spot area for the PTEN gene. Four mutations were novel. A wide range of phenotypic and genotypic spectra was found in our study group. CONCLUSION: Screening of PTEN mutations in patients with macrocephaly is recommended due to an increased risk of cancer. Further cases are needed to make a phenotype-genotype correlation in PHTS.

Fetal Gene Therapy Using a Single Injection of Recombinant AAV9 Rescued SMA Phenotype in Mice.

Symptoms of spinal muscular atrophy (SMA) disease typically begin in the late prenatal or the early postnatal period of life. The intrauterine (IU) correction of gene expression, fetal gene therapy, could offer effective gene therapy approach for early onset diseases. Hence, the overall goal of this study was to investigate the efficacy of human survival motor neuron (hSMN) gene expression after IU delivery in SMA mouse embryos. First, we found that IU-intracerebroventricular (i.c.v.) injection of adeno-associated virus serotype-9 (AAV9)-EGFP led to extensive expression of EGFP protein in different parts of the CNS with a great number of transduced neural stem cells. Then, to implement the fetal gene therapy, mouse fetuses received a single i.c.v. injection of a single-stranded (ss) or self-complementary (sc) AAV9-SMN vector that led to a lifespan of 93 (median of 63) or 171 (median 105) days for SMA mice. The muscle pathology and number of the motor neurons also improved in both study groups, with slightly better results coming from scAAV treatment. Consequently, fetal gene therapy may provide an alternative therapeutic approach for treating inherited diseases such as SMA that lead to prenatal death or lifelong irreversible damage.

Melanocortin 4 receptor (MC4R) gene variants in children and adolescents having familial early-onset obesity: genetic and clinical characteristics.

Melanocortin 4 receptor gene plays an important role in food intake, energy balance, and weight control. The autosomal dominantly inherited MC4R variants cause obesity by causing hyperphagia and decreased sense of satiety. Homozygous variants are rarely reported, and they cause earlier/severe obesity. Our objective is to determine the MC4R gene variant frequency in children and adolescents with familial early-onset obesity. One hundred thirty-nine children and adolescents (57 girls/82 boys) whose weight increase started before the age of 5 years and who had early-onset obesity in at least one of their first-degree relatives were included in the study. Obesity is defined as body mass index (BMI) of ≥ 95th percentile, and as extreme obesity is defined if the BMI ≥ 120% of the 95th percentile or ≥ 35 kg/m2. Children having genetic syndromes associated with obesity and mental retardation or taking drugs that promote changes in eating behavior or weight were excluded from the study. Coding region of the MC4R gene was sequenced by using the Illumina MiSeq Next Generation Sequencing System. The mean age of the patients was 7.3 ± 3.7 years, and the mean BMI SDS was 3.7 ± 0.7. While 118 patients (85%) were prepubertal, 21 patients (15%) were pubertal. Seven different variants were identified in 12 patients by giving a variant detection rate of 8.6%, of these five were previously identified missense variants p.N274S, p.S136F, p.V166I, p.R165W, and p.I291SfsX10. One homozygous variant p.I291SfsX10 (c.870delG) was detected in a severely obese 2-year-old boy, and other variants were heterozygous. Two novel variants were found: p.M200del and p.S188L. By using the in silico analysis software, these novel variants were predicted to be disease causing.Conclusion: MC4R gene variants are quite common in childhood obesity in Turkish population. Screening the variants in MC4R gene is necessary in patients with severe childhood-onset obesity. In such patients, comorbidities of obesity can be seen from early years. What is known • The frequency of MC4R mutations in obese patients was approximately 0-6.3%. What is new • In obese Turkish pediatric population, unlike other European countries, MC4R gene variants are quite common as we found a variant rate of 8.6% • We believe it is necessary to screen the variants in MC4R gene in patients with severe childhood-onset obesity and who had early-onset obesity in at least one of their first-degree relatives in Turkish population.

Chronic granulamatous disease: Two decades of experience from a paediatric immunology unit in a country with high rate of consangineous marriages.

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by susceptibility to bacterial and fungal infections resulting from the inadequacy of phagocytic leucocytes to produce reactive oxygen radicals. CGD is a genetically heterogeneous disease with an X-linked recessive (XR-CGD) form caused by mutations in the CYBB (OMIM #300481) gene encoding the gp91(phox) protein, and an autosomal recessive (AR-CGD) form caused by mutations in the CYBA (OMIM #608508), NCF1 (OMIM #608512), NCF2 (OMIM #608515) and NCF4 (OMIM #601488) genes encoding p22(phox), p47(phox), p67(phox) and p40(phox), respectively. The genetic mutation of one of the cytosolic p47phox/p67phox proteins and membrane-bound gp91phox/p22phox proteins, which constitutes the NADPH oxidase enzyme complex, causes the disease. In this study, we evaluated the clinical, laboratory and genetic findings and the prognostic effects of molecular inheritance of our 24 CGD cases (14 XR, 10 autosomal recessive-AR). Consanguinity (three XR and all AR cases) showed statistically significant relationship with the type of hereditary inheritance (P < 0.001). 83% patients had an infection since early infancy. The mean age of initiation of symptoms was earlier in XR cases, and 78% patients had respiratory tract infections. Bone marrow transplantation was performed in five XR cases (two ex) and four AR (one ex) cases. Three of nine XR and two of six AR cases deceased on medical follow-up. In countries especially with high consanguinity rates, the early diagnosis for appropriate prophylactic treatment of CGD is quietly important to avoid from recurrent severe infections, early death and fatal complications of late transplantation.

Evaluation of CNTNAP2 gene rs2107856 polymorphism in Turkish population with pseudoexfoliation syndrome.

PURPOSE: To investigate rs2107856 single-nucleotide polymorphism (SNP) of CNTNAP2 gene in Turkish population with pseudoexfoliation and to correlate clinical characteristics with the genotypic profile. MATERIALS AND METHODS: Forty-three patients with pseudoexfoliation syndrome (PXS), 46 patients with pseudoexfoliation glaucoma (PXG) and 99 healthy controls were enrolled. Comprehensive ophthalmological examination, central corneal thickness measurement and retinal nerve fiber layer thickness analysis of the peripapillary area were performed. Blood samples of 2 mL with EDTA were obtained and sent for genetic analysis. The role of the detected polymorphism on disease tendency along with the genotype and allele frequencies in each group was evaluated. RESULTS: The mean age of the groups was 70.0 ± 8.0 (range 51-86) in PXS, 71.2 ± 8.8 (range 51-93) in PXG and 64.6 ± 8.3 (range 51-91) in controls. The percentages of homozygote individuals were 11.6, 10.9, 21.2%, and heterozygote individuals were 41.9, 45.7, 42.4% in patients with PXS, PXG and controls, respectively. There was no statistically significant difference between groups in terms of both genotype and allele frequencies of rs2107856 (p = 0.429 and p = 0.178, respectively). Retinal nerve fiber layer thickness did not differ between SNP-positive and SNP-negative individuals in PXG, and there was no significant difference between genotype and age, sex, best corrected visual acuity, intraocular pressure, central corneal thickness, cup/disk ratio and retinal nerve fiber layer thickness in any of the groups (p > 0.05). CONCLUSION: rs2107856 SNP of CNTNAP2 gene has no association with PXS and PXG in the evaluated Turkish population.

HAX1 mutation positive children presenting with haemophagocytic lymphohistiocytosis.

The genetic basis of haemophagocytic lymphohistiocytosis (HLH) has not been elucidated in 10% of affected patients. In this study, we report four HLH episodes in three patients with HAX1 gene mutations. We screened the mutations associated with congenital neutropenia (CN) because the neutropenia persisted following HLH treatment. There were homozygous HAX1 mutations detected in all patients. This is the first case series of patients with CN caused by HAX1 mutation who presented with HLH. We hypothesize that severe neutropenia persists after an HLH episode in children without HLH mutations (especially infants) because these patients have CN caused by HAX1 mutations.

LOXL1 gene analysis in Turkish patients with exfoliation glaucoma.

The purpose of this study is to evaluate whole lysyl oxidase like 1 (LOXL1) gene by sequence analysis in Turkish patients with exfoliation glaucoma (XFG). A total of 48 (35 male, 13 female) patients with XFG were enrolled. Besides routine ophthalmological examination, peripapillary retinal nerve fibre layer (RNFL) analysis with optic coherence tomography was performed. Blood samples of 2 ml with EDTA were obtained and sent to Medical Genetics Department, Molecular Genetics Laboratory for LOXL1 polymorphism (PCR and agarose gel imaging) analysis. The role of the detected changes on disease severity was evaluated. No LOXL1 gene mutations in any of the patients were detected. Three types of single-nucleotide polymorphisms (SNPs) including R141L(rs1048661), A320A(rs41435250), and F184F were detected in 17 (35.3 %) patients. When compared, SNP-positive patients had thinner RNFL than SNP-negative patients (64.5 ± 17.6 and 66.1 ± 20.4 µ, respectively), and SNP-positive patients had higher cupping/disc ratio than SNP-negative patients (0.76 ± 0.2 and 0.70 ± 0.3, respectively). However, both values were not statistically significant (p = 0.966 and p = 0.539, respectively). When compared, R141L-positive patients had significantly thinner cornea thickness (516.11 ± 30.3 µ) than R141L-negative patients (556.69 ± 27.2 µ) (p = 0.004). There was not any statistical significant difference in the means of age, gender, BCVA, MD, PSD, IOP, number of hypotensive agents, and percent of glaucoma surgery (p > 0.05). In this study group of Turkish population, no LOXL1 mutations were found. No associations between the defined SNPs (A320A, R141L and F184F) and the severity of the disease were detected.

Clinical Variability in a Family with Noonan Syndrome with a Homozygous PTPN11 Gene Variant in Two Individuals

Objective: Noonan syndrome (NS) is characterized by dysmorphic facial features, short stature, congenital heart defects, and varying levels of developmental delays. It is a genetic, multisystem disorder with autosomal dominant inheritance and is the most common of the RASopathies. In approximately 50% of patients, NS is caused by variants in the Protein Tyrosine Phosphatase Non-Receptor Type 11 (PTPN11) gene. The aim of this study was to evaluate two patients with a previously reported PTPN11 homozygous variant for the first time and seven other kindred members carrying the same heterozygous variant in terms of clinical, biochemical, genetic, and response to treatment. Methods: Nine patients diagnosed with NS due to the same variants in the PTPN11 gene were included in the study. Results: The median (range) age at diagnosis was 11.5 (6.8-13.9) years and the mean follow-up duration was 4.7 (1-7.6) years. In eight patients (88.9%), short stature was present. The height standard deviation score of the patients on admission was -3.24±1.15. In six of the patients, growth hormone treatment was initiated. Cardiovascular or bleeding disorders were not detected in any of the patients. Three (33.3%) had hearing loss, two (22.2%) had ocular findings and one (11.1%) had a horseshoe kidney. The mean psychomotor development performance score was 84.03±17.09 and the verbal score was 82.88±9.42. Genetic analysis revealed a variant in the PTPN11 gene [c.772G>A; (p.Glu258Lys)] that had been previously described and was detected in all patients. Two patients were homozygous for this variant and short stature was more severe in these two. Conclusion: A previously described in PTPN11 affected nine members of the same kindred, two with homozygous inheritance and the remainder being heterozygous. To the best of our knowledge, these are the first homozygous PTPN11 case reports published, coming from two related consanguineous families.

Current genetic defects in common variable immunodeficiency patients on the geography between Europe and Asia: a single-center experience.

Identification of the causes of monogenetic common variable immunodeficiency (CVID) patients has rapidly increased in the last years by means of worldwide availability of appropriate genetic diagnostic methods. However, up to date, very limited numbers of reports demonstrating the role of geography, ethnicity, and consanguinity have been published. Here, we reported the first study of Turkish CVID patients and compared them with the results of three countries from America, Europe, and Asia. A total of 100 children diagnosed as CVID according to the criteria of European Society for Immunodeficiencies were enrolled, and they were genetically analyzed by using targeted next-generation sequencing and whole-exome sequencing. The median age of our patients was 5.8 years (range, 3.0-16.0 years) at clinical diagnosis and 9.0 years (range, 4.8-21.0 years) at the time of genetic diagnosis. The consanguinity rate was 24%. Disease-causing pathogenic variants were defined in 40% of patients in a total of 17 different genes. Sixteen of 40 identified pathogenic variants were novel (40%). We determined 18 surface molecular defects, 10 cytosolic defects, 9 nuclear defects, and 3 others. In our cohort, the most common gene was TACI (15/40 in pathogenic variant identified cases and 15/100 in all cases) followed by the others such as PLCÒ¯2, LRBA, TCF3, and STAT1. In contrast to our expectations, our results were more similar to American and European population rather than Asians, although we also have high consanguinity rates and live on the geography between Europe and Asia. Genetic investigation is a great challenge, because of the complexity and heterogeneity of the disease, and each country has to know their own current genetic landscape in CVID for a better and successful management of the patients.

Experience with carnitine palmitoyltransferase II deficiency: diagnostic challenges in the myopathic form.

OBJECTIVES: Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal recessive disorder of long-chain fatty acid oxidation. Three clinical phenotypes, lethal neonatal form, severe infantile hepatocardiomuscular form, and myopathic form, have been described in CPT II deficiency. The myopathic form is usually mild and can manifest from infancy to adulthood, characterised by recurrent rhabdomyolysis episodes. The study aimed to investigate the clinical features, biochemical, histopathological, and genetic findings of 13 patients diagnosed with the myopathic form of CPT II deficiency at Ege University Hospital. METHODS: A retrospective study was conducted with 13 patients with the myopathic form of CPT II deficiency. Our study considered demographic data, triggers of recurrent rhabdomyolysis attacks, biochemical metabolic screening, and molecular analysis. RESULTS: Ten patients were examined for rhabdomyolysis of unknown causes. Two patients were diagnosed during family screening, and one was diagnosed during investigations due to increased liver function tests. Acylcarnitine profiles were normal in five patients during rhabdomyolysis. Genetic studies have identified a c.338C>T (p.Ser113Leu) variant homozygous in 10 patients. One patient showed a novel frameshift variant compound heterozygous with c.338C>T (p.Ser113Leu). CONCLUSIONS: Plasma acylcarnitine analysis should be preferred as it is superior to DBS acylcarnitine analysis in diagnosing CPT II deficiency. Even if plasma acylcarnitine analysis is impossible, CPT2 gene analysis should be performed. Our study emphasizes that CPT II deficiency should be considered in the differential diagnosis of recurrent rhabdomyolysis, even if typical acylcarnitine elevation does not accompany it.

Primary immune regulatory disorders (PIRD): expanding the mutation spectrum in Turkey and identification of sixteen novel variants.

Human Inborn Errors of Immunity (IEIs) encompass a clinically and genetically heterogeneous group of disorders, ranging from mild cases to severe, life-threatening types. Among these, Primary Immune Regulatory Disorders (PIRDs) constitute a subset of IEIs characterized by diverse clinical phenotypes, prominently featuring severe atopy, autoimmunity, lymphoproliferation, hyperinflammation, autoinflammation, and susceptibility to malignancies. According to the latest report from the International Union of Immunological Societies (IUIS), PIRDs arise from mutations in various genes including LYST, RAB27A, AP3B1, AP3D1, PRF1, UNC13D, STX11, STXBP2, FAAP24, SLC7A7, RASGRP1, CD70, CTPS1, RLTPR, ITK, MAGT1, PRKCD, TNFRSF9, SH2DIA, XIAP, CD27 (TNFRSF7), FAS (TNFRSF6), FASLG (TNFSF6), CASP10, CASP8, FADD, LRBA, STAT3, AIRE, ITCH, ZAP70, TPP2, JAK1, PEPD, FOXP3, IL2RA, CTLA4, BACH2, IL2RB, DEF6, FERMT1, IL10, IL10RA, IL10RB, NFAT5, TGFB1, and RIPK1 genes. We designed a targeted next-generation sequencing (TNGS) workflow using the Ion AmpliSeq™ Primary Immune Deficiency Research Panel to sequence 264 genes associated with IEIs on the Ion S5™ Sequencer. In this study, we report the identification of 38 disease-causing variants, including 16 novel ones, detected in 40 patients across 15 distinct PIRD genes. The application of next-generation sequencing enabled rapid and precise diagnosis of patients with PIRDs.