High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population.

Neurodevelopmental disorders (NDDs) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDDs is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic "disease-associated genes" molecular etiology and biology of NDDs; however, the majority of NDDs remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDDs. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176 = 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROHs) - reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey.

Exploiting spatial heterogeneity and response characterization in non-uniform architected materials inspired by slime mould growth.

Inspired by shape-shifting features of slime mould growth, we implement a computational algorithm to study the nutrient-induced pattern formation and transition of slime mould. We then translate the learned principles into the design and characterization of cellular materials, with particular focus on the issue of spatial heterogeneity due to the nature of the non-uniform, asymmetric pattern. Guided by clustering analysis, compression tests on 3D-printed samples, and numerical simulations by finite element models, we were able to categorize patterns with certain geometric features (such as layout and symmetry) and found similar mechanical response features, indicating high tailorability of non-uniform architected materials. This study paves the road for the advanced computer-aided design of architected materials and its potential in the development of innovative engineering mechanical devices and structural systems.

The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance.

Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.

Collapsing Glomerulopathy in a Child with Galloway-Mowat Syndrome.

Galloway-Mowat syndrome (GMS) is an autosomal recessive disorder with a poor prognosis that was first defined as a triad of central nervous system involvement, hiatal hernia, and nephrotic syndrome. However, this syndrome is now known to have a heterogeneous clinical presentation. The nephrotic syndrome is steroid resistant and is responsible for the outcome. The combination of collapsing glomerulopathy and GMS is very rare. A 26-month-old boy presented with steroid-resistant nephrotic syndrome associated with neurologic findings, including microcephaly, psychomotor retardation, and nystagmus. Magnetic resonance imaging showed marked cerebral atrophy, optic atrophy, and hypomyelination. A renal biopsy was consistent with collapsing glomerulopathy. If collapsing glomerulopathy is associated with neurological abnormalities, especially with microcephaly, clinicians should consider GMS as a possible underlying cause.

Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.

Development of the human nervous system involves complex interactions among fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families and homozygous loss-of-function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations.

Existe uma relação entre a artrite gotosa e as mutações genéticas da febre familiar do Mediterrâneo? / Is there a relationship between gouty arthritis and Mediterranean fever gene mutations?

RESUMOObjetivoA artrite gostosa e a febre familiar do Mediterrâneo (FFM) compartilham algumas características clínicas e patológicas, como ser classificada como uma doença autoimune inflamatória, ter associação com o inflamassoma, manifestar artrite intermitente de curta duração e boa resposta a tratamentos com colchicina e anti-interleucina-1. Como o gene da febre familiar do Mediterrâneo (MEFV) é o fator causador da FFM, este estudo teve como objetivo investigar a prevalência de mutações do gene MEFV e seu efeito sobre as manifestações da doença em pacientes turcos com artrite gotosa.MétodosForam incluídos no estudo 97 pacientes com diagnóstico de artrite gotosa primária (93 M e 4 F; 54 [37-84] anos) e 100 controles saudáveis (94 M e 6 F; 57 [37-86] anos). Todos os indivíduos foram submetidos à análise do genótipo à procura de variações no MEFV. Também foi registrado o número de crises de gota, o uso de diuréticos e a história de nefrolitíase e presença de tofos.ResultadosA frequência de portadores de mutações no MEFV em pacientes e controles foi de 22,7% (n = 22) e 24% (n = 24), respectivamente. A comparação entre os pacientes e os controles não produziu diferença estatisticamente significativa em termos de frequência de portadores de mutações no MEFV (p = 0,87). As frequências alélicas de mutações no MEFV nos pacientes foram de 11,9% (n = 23) e 14% (n = 28) nos controles (p = 0,55). A presença de variantes do MEFV não mostrou qualquer associação com as características clínicas da artrite gotosa. A análise por subgrupos de pacientes revelou que aqueles com artrite gotosa com mutações tinham frequências semelhantes de tofo, história de nefrolitíase e podogra em comparação com os indivíduos sem mutações (p > 0,05).ConclusõesAs mutações no gene MEFV não exercem um papel relevante em pacientes turcos com artrite gotosa.

ABSTRACTObjectiveGouty arthritis and familial Mediterranean fever share some clinical and pathological features such as being classified as auto-inflammatory disease, association with inflammasome, short-lived intermittent arthritis, and good response to colchicine and anti-interleukin-1 treatments. As Mediterranean fever gene is the causative factor of familial Mediterranean fever, we aimed to investigate the prevalence of Mediterranean fever gene mutations and their effect on disease manifestations in Turkish gouty arthritis patients.MethodsNinety-seven patients diagnosed with primary gouty arthritis (93 M and 4 F, 54 [37–84] years) and 100 healthy controls (94 M and 6 F, 57 [37–86] years) were included in the study. All subjects were genotyped for the Mediterranean fever gene variations. Number of gout attacks, diuretic use, history of nephrolithiasis and presence of tophus were also recorded.ResultsThe carriage rate of Mediterranean fever mutations for patients and controls was 22.7% (n = 22) and 24% (n = 24), respectively. The comparison of the patient and control groups yielded no significant difference in terms of the Mediterranean fever mutations’ carriage rate (p = 0.87). The allelic frequencies of the Mediterranean fever mutations in patients were 11.9% (n = 23) and 14% (n = 28) in controls (p = 0.55). The presence of Mediterranean fever variants did not show any association with clinical features of gouty arthritis. The subgroup analysis of patients revealed that gouty arthritis patients with mutations had similar frequencies of tophus, history of nephrolithiasis and podagra compared to the ones without mutations (p > 0.05).ConclusionsThis study does not provide support for a major role of Mediterranean fever mutations in Turkish gouty arthritis patients.

A new mutation in blau syndrome.

Blau syndrome is a rare, autosomal dominant, granulomatous autoinflammatory disease. The classic triad of the disease includes recurrent uveitis, granulomatous dermatitis, and symmetrical arthritis. Blau syndrome is related to mutations located at the 16q12.2-13 gene locus. To date, 11 NOD2 gene mutations causing Blau syndrome have been described. Here, we describe a 5-year-old male patient who presented with Blau syndrome associated with a novel sporadic gene mutation that has not been reported previously.

[Is there a relationship between gouty arthritis and Mediterranean fever gene mutations?]. / Existe uma relação entre a artrite gotosa e as mutações genéticas da febre familiar do Mediterrâneo?

OBJECTIVE: Gouty arthritis and familial Mediterranean fever (FMF) share some clinical and pathological features such as being classified as auto inflammatory disease, association with inflammasome, short-lived intermittent arthritis, and good response to colchicine and anti-interleukin-1 treatments. As Mediterranean fever (MEFV) gene is the causative factor of FMF, we aimed to investigate the prevalence of MEFV gene mutations and their effect on disease manifestations in Turkish gouty arthritis patients. METHODS: Ninety-seven patients diagnosed with primary gouty arthritis (93M and 4 F, 54 [37-84] years) and 100 healthy controls (94M and 6 F, 57 [37-86] years) included in the study. All subjects were genotyped for the MEFV variations. Number of gout attacks, diuretic use, and history of nephrolithiasis and presence of tophus were also recorded. RESULTS: The carriage rate of MEFV mutations for patients and controls were 22.7% (n=22) and 24% (n=24) respectively. The comparison of the patient and control groups yielded no significant difference in terms of the MEFV mutations carriage rate (p=0.87). The allelic frequencies of the MEFV mutations in patients were 11.9% (n=23) and 14% (n=28) in controls (p=0.55). The presence of MEFV variants did not show any association with clinical features of gouty arthritis. The subgroup analysis of patients revealed that gouty arthritis patients with mutations had similar frequencies of tophus, history of nephrolithiasis and podogra compared to the ones without mutations (p>0.05). CONCLUSIONS: This study does not provide support for a major role of MEFV mutations in Turkish gouty arthritis patients.

Heterotopic brain tissue on the face and neck in a neonate: a rare case report and literature review.

Heterotopic brain tissue (HBT) most commonly occurs in the nasal region and it is often referred to as a nasal glioma. Nonnasal locations for ectopic brain tissue are less commonly described. In English literature, only six cases have been reported that share some features (face or neck location) of this case. The presented case is the fourth case, located in both face and neck, and the one, which is the most extensive with its dimensions. According to location of heterotopic brain may lead to dystocia. We reported HBT of the face and neck in a neonate and the differential diagnosis, etiopathogenic mechanisms and clinical courses are reviewed and discussed.

Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene.

BACKGROUND: Ellis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance. METHODS: Because of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the EVC/EVC2 locus. The results did not exclude linkage, so samples were sequenced for mutations. RESULTS: We identified a c.1868T>C mutation in EVC, which predicts p.L623P, and was homozygous in affected individuals. CONCLUSION: We conclude that this EVC mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. EVC mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome.

Adipose tissue 11-beta-Hydroxysteroid Dehydrogenase Type 1 and Hexose-6-Phosphate Dehydrogenase gene expressions are increased in patients with type 2 diabetes mellitus.

AIMS: We have determined 11-beta-Hydroxysteroid Dehydrogenase Type 1 (HSD11B1) and Hexose-6-Phosphate Dehydrogenase (H6PD) mRNA expression levels in adipose tissues from patients with type 2 diabetes mellitus. METHODS: Six non-diabetic and seven diabetic male patients who undergo elective abdominal surgery were included in the study and visceral and subcutaneous adipose tissue samples were obtained. Fresh preadipocyte cultures were administered to low and high glucose medium (11M and 25M) in vitro for 24h and mRNA extractions were performed. HSD11B1 and H6PD gene mRNA expression levels were determined by real-time PCR and compared. Glyceraldehyde-3-phosphate Dehydrogenase (G3PD) mRNA level is used as housekeeping gene expression. RESULTS: HSD11B1 mRNA levels were significantly higher in patient with T2DM than controls in both visceral and subcutaneous adipose tissues (3.35+/-0.7 vs. 0.37+/-0.1; P=0.01 and 2.07+/-0.8 vs. 0.11+/-0.05; P=0.01, respectively). H6PD mRNA levels were also significantly higher in patient with T2DM than controls in both visceral and subcutaneous adipose tissues (3.95+/-1.2 vs. 1.95+/-0.8; P=0.050 and 2.23+/-1.1 vs. 0.46+/-0.1; P=0.043, respectively). CONCLUSIONS: Failure to down-regulate HSD11B1 activity in patients with type 2 diabetes may contribute to the pathogenesis of T2DM. Subcutaneous and visceral adipose tissues similarly exhibit the same variation in patients with type 2 diabetes mellitus.

Electronic microarray screening of podocin mutations: a single-center study.

BACKGROUND: Because of resistance to immunosuppressants in nephrotic syndrome and reduction of proteinuria relapses following renal transplantation, it seems that new horizons have arisen from mutational screening of the podocin gene. The aim of this study was to assess electronic microarray screening of the podocin mutation. METHODS: Twelve previously identified podocin mutations were screened by the electronic microarray method in known DNA samples and in patients (aged 5 months-18 years, n = 38) with steroid-resistant primary nephrotic syndrome, isolated proteinuria, end-stage renal disease secondary to idiopathic nephrotic syndrome, and proteinuria relapses following renal transplantation. RESULTS: DNA samples previously supplied to define the mutation profile for analysis and which were used as controls were completely and correctly detected by this method. None of the 12 mutations was detected in our patients. The duration of analysis for one mutation, including hybridization, was only 30 min for 38 cases. CONCLUSION: Electronic microarray screening for NPHS2 mutations is not only rapid but also accurate. Previous identification of the mutation profile most often encountered in the investigated population is needed, however.

Evaluation of the relationship between C677T variants of methylenetetrahydrofolate reductase gene and hyperhomocysteinemia in children receiving antiepileptic drug therapy.

Homocysteine (Hcy) is a sulfur-containing amino acid involved in methionine metabolism. Elevated plasma Hcy concentration is a possible risk factor for vascular disease. Folate and vitamin B-12 are vitamins that are necessary for remethylization of Hcy to methionine. The methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in remethylation of Hcy to methionine and supplies the required 5-methyltetrahydrofolate as the methyl donor for this reaction. It is well known that some antiepileptic drugs (AED) can lead to hyperhomocysteinemia by affecting the levels of folate and vitamin B-12. The C677T variant of MTHFR gene can also lead to hyperhomocysteinemia particularly when serum folate level is decreased. In this study, we investigated the levels of serum folate, vitamin B-12 and Hcy in epileptic patients receiving carbamazepine (CBZ) or valproic acid (VPA) as monotherapy, and we also evaluated the probable contribution of the C677T variant of MTHFR gene in hyperhomocysteinemia. A total of 93 patients with idiopathic epilepsy receiving CBZ or VPA as monotherapy were included in this study. CBZ and VPA groups consisted of 29 and 64 patients, respectively. The control group comprised 62 healthy children. We measured serum folate, vitamin B-12 and Hcy levels in each group. We found that mean serum folate level was statistically lower and mean Hcy level was higher in epileptic patients receiving CBZ or VPA when compared with those of controls'. We also determined the C677T variants of MTHFR gene (as normal, heterozygote or homozygote) in epileptic patients. We compared the variant groups for serum folate, vitamin B-12 and Hcy levels and found no significant differences among them. In conclusion, C677T variants of MTHFR gene have no contribution in hyperhomocysteinemia in epileptic patients receiving CBZ or VPA.

A very frequent mutation and remarkable association of R761H with M694V mutations in Turkish familial Mediterranean fever patients.

Familial Mediterranean fever (FMF) is an autosomal-recessive disease. It is characterized by recurring fever, abdominal pain, and serositis. The Mediterranean fever (MEFV) gene is localized on 16p13.3 and more than 35 mutations have been described to date. There are some differences in the gene mutations of FMF in the various ethnic groups. The aim of this study is to determine the frequency of the mutations which has been reported comparatively rare, to define the most effective mutation set, and to select the most suitable DNA analysis system for Turkish FMF patients. Mutations in 330 Turkish FMF patients with typical phenotypes from various regions of Turkey were evaluated for the research purposes. These patients were analyzed for six MEFV gene mutations by the NanoChip Molecular Genetics Workstation. The most frequent mutation was M694V, identified in 50.00% of the alleles examined; M680I followed with 14.10% and V726A--9.70%. Consequently, we determined that R761H (n = 23; 3.48%) was the most frequent rare mutations in Turkish FMF patients. Frequency of the rare mutations were R761H (3.48%), E148Q (1.36%), and M694I (1.21%). All of these mutations were in the compound heterozygote state. Our study showed that R761H mutations were higher than it has been reported in literature until now and were mainly associated with M694V. We suggest that mutation R761H should be included in the mutation scanning analysis researches or considered if the patient has M694V/? mutation especially in Turkish FMF patients. Larger serial studies need to be done to investigate the rate and coexistence of these mutations.

The rate of pyrin mutations in critically ill patients with systemic inflammatory response syndrome and sepsis: a pilot study.

OBJECTIVE: The role of individual genetic differences in susceptibility to systemic inflammatory response syndrome (SIRS) and sepsis is generally unrecognized or underestimated. We investigated the rate of pyrin mutations in critically ill patients with SIRS and sepsis, and compared whether carriers for pyrin mutations are associated with respect to the frequency of and certain features of sepsis and SIRS. METHODS: We tested M694V, M680I, V726A, R761H, and M694I mutations in critically ill patients. RESULTS: Twenty-four of 80 (30%) critically ill patients were found to carry some pyrin mutations; none had a history compatible with familial Mediterranean fever. We also found a high frequency of carriers in patients having pneumonia (30.3%), urinary tract infection (29.4%), and acute pancreatitis (30.8%). When we compared our results with the pyrin mutation carrier rate of a healthy Turkish population (10%), the rate of pyrin mutations in all patients (p < 0.001), and patients with urinary tract infection (p <0.001), acute pancreatitis (p <0.001), and pneumonia (p < 0.001) were found to be significantly high. The white blood cell count, erythrocyte sedimentation rate, lactic dehydrogenase, and rate of fever and pulse were significantly higher, whereas systolic and diastolic blood pressure and albumin levels were significantly lower in patients with pyrin mutation compared to those without the mutation. CONCLUSION: Our results showed that critically ill patients with SIRS and sepsis have increased prevalence of pyrin mutations, and patients with SIRS and sepsis carrying the pyrin mutation seem to be highly susceptible for a severe disease course.

Caudothalamic groove cysts in Zellweger syndrome.

The cerebro-hepato-renal syndrome of Zellweger is the most severe peroxisome biogenesis disorder. Zellweger syndrome is caused by a disturbance in the peroxisomal protein import machinery and leads to multiple organ defects and death usually within the first year of life. Here we report a 3-month-old girl with Zellweger syndrome who was found to have cysts in the caudothalamic groove on cranial magnetic resonance imaging.