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Objective: Neurofibromatosis type 1 (NF1, #162200) is a common neurological disorder with de novo or inherited germline mutations of the Neurofibromin (NF1, *613113). The purpose of this study is to increase the limited knowledge of NF1 in a small population-based dataset. Materials and Methods: This study enrolled patients with clinically suspected NF1 referred to the Kayseri Training and Research Hospital, Medical Genetics Department, between 2015 and 2017. The local ethics committee approved this study. Next-generation sequencing was performed for the genetic analysis. The genetic, demographic, and clinical features of the participants were characterized. Results: A total of 79 cases of NF1 were included. Of these cases, 40 were male, and 39 were female. The mean age was 11.9 years, and most were younger than 18 years. The most common complaint was café au lait macules. The 61 (77.3%) patients had pathogenic variants, and 16 (26.2%) were novel. Mostly affected mutation sites were exonic regions (n=54, 88.5%). The most common mutated exon was exon 38 (n=7, 11.5%), and most of the detected mutations were nonsense mutations (31%). Conclusion: It is one of Türkiye's largest NF1 study groups, where all exons of the NF1 gene were analyzed. This study contributes novel variants to the literature. There was no mutational hotspot region, and no significant relationship between genotype and phenotype was observed. Further studies and large sample sizes are required to better understand the relationship between NF and genetic changes. [ABSTRACT FROM AUTHOR]

Beaulieu‐Boycott‐Innes syndrome (BBIS; MIM#613680) is a rare, autosomal recessive neurodevelopmental genetic disorder associated with pathogenic variants in the THOC6 gene (*615403). Intellectual disability, dysmorphic facial features, developmental delay, structural cardiac and genitourinary anomalies, and dental caries are suggestive findings of the syndrome. Exome sequencing (ES) may facilitate the diagnosis of this syndrome, whose clinical features can be nonspecific. Here we report a BBIS patient with a homozygous truncating variant (NM_024339.5:c.299G>A; p.Trp100Ter) in the THOC6 gene, diagnosed by ES analysis. The patient's variant is novel and some features such as clivus dysplasia, occult spina bifida, tapered fingers, and upturned fleshy earlobes have not been reported in the literature before. This new case report will expand the knowledge of BBIS and provide more information about the genetic variants and phenotypic spectrum. Also, new cases with THOC6 variants will define the core clinical features and common phenotypes of the BBIS over time. [ABSTRACT FROM AUTHOR]

Consanguineous marriages cause rare blended phenotypes in common geographies and the emergence of different homozygous diseases in the same family. In this article, a family in which different rare mechanisms come together as a result of consanguineous marriage is presented. A 2-yearold proband with a blended phenotype with sex development disorder and coenzyme Q10 deficiency has psychomotor retardation, micropenis, undescended testicles, dysmorphic findings, hypotonia, and the gonads have a bilateral testicular appearance and are located in the inguinal canal. In the patient's brother, who previously died due to hydrocephalus, a non-sense homozygous variant c.1051C>T p.(Arg351*) was detected in the 7th exon of the NM_001134830 transcript of the AHI1 gene. The patient's cytogenetic analysis result is: 46,XX,ish,der(X)t(X;Y)(p22.3;p11.2)(SRY+). In the molecular karyotyping analysis performed due to hypotonia, psychomotor retardation and dysmorphic findings; a change of 2.1 Mb in size was detected in the Xp22.33p22.32 region and 3.1 Mb in size in the Yp11.2 region. This change is 46,XX sex reversal 1; it has been associated with SRXX1 (OMIM number:#400045) disease. In the subsequent whole exome analysis, a c.437T>G (Phe146Cys) missense homozygous probable pathogenic variant was detected in the NM_016035 transcript in the 5th exon of the COQ4 gene, which explains other clinical findings. In primary deficiency of coenzyme Q10 (OMIM number: #616276), which is a lipid component of the mitochondrial respiratory chain, symptoms vary; hypotonia, decreased coQ levels in muscle tissue, regression in psychomotor development, seizures, and increased serum lactate levels are observed. It is generally lethal in the first years of life, and in this respect, it is thought that the clinical findings of the proband will contribute to the literature with their milder course. To our knowledge, there is no other case in the literature reporting a sexual development anomaly or primary CoQ10 deficiency. [ABSTRACT FROM AUTHOR]

Hereditary hyperekplexia (HPX), a neuronal disorder caused by genetic defects leading to dysfunction of glycinergic inhibitory transmission, is mainly characterized by startle responses to unexpected sensory stimuli and stiffness. HPX, a rare and underdiagnosed disorder, is manifest after birth and commonly improves with age. Establishing the correct diagnosis early is essential so that proper management may be initiated to reduce the risk of complications, such as potentially life-threatening apnea during episodes of stiffness. Defects in GLRA1 are the most common cause of HPX, inherited both in an autosomal dominant and autosomal recessive manner. Sequence analysis (95%) is the main method for detection of pathogenic variants of probands. Also copy number variations (CNVs) (5%) plays role in etiology. We here report independent three Turkish patients with hyperekplexia which stems from GLRA1 related phenotypes and we confirm mostly known genetic background of HPX by different methods in our outpatient clinic. Whole exome sequencing-CNV, microarray analysis revealed that previously reported homozygous deletion of exons 1-7 of the GLRA1 gene in patient 1. This genetic changes thought to be probably the founder mutation in Turkish-Kurdish populations. In patient 2, homozygous c.277C>T p.Arg93Trp variant in the GLRA1 gene was found. In patient 3, microarray analysis revealed a 299 kb deletion at the q33.1 region of the chromosome 5 which is GLRA1 gene located in. The fact that the results of three unrelated patients in one center can be considered in terms of planning the examination for deletion/duplication analyzes first in patients with GLRA1-related phenotypes in the Turkish population. [ABSTRACT FROM AUTHOR]

One of the important causes of severe neuromotor developmental delay and epilepsy is malformations of cortical development (MCD) such as pachygyria, lissencephaly. Genes involved in neuronal cell proliferation, migration and post-migration cortical organization have been implicated in MCD. The CAMPAS1 gene, which provides microtubule and spectrin binding activity, is one of the rare causes that have been recently identified. Another rare cause of severe neuromotor developmental delay and epilepsy is he NBEA gene. It encodes the neurobeachin protein, a neuro-specific structural protein that plays a role in vesicle traffic and synaptic structure. In this study, we present a case with loss of function variant in these two rare genes. A proband 7-year-old female patient, only child of consanguineous parents, microcephaly, seizure, infantile spasm, neurodevelopmental retardation, hypotonia, pachygyria, corpus callosum agenesis, hypoplasia of the brain stem, spasticity in the extremities, nutrition problems, recurrent respiratory tract infection findings. Whole exome analysis of the patient revealed c.1153C>T p.Gln385* non-sense homozygous likely pathogenic pathogenic variant in CAMSAP1 gene and de novo c.6867G>A p.Trp2289* non-sense heterozygous pathogenic variant in NBEA gene. We considered it as a blended phenotype. In the literature, the case of these two genes together has not been reported before. There are limited case reports with these two genes. For this reason, it is thought that it will contribute to the literature. In this study, we emphasize that in the presence of complex and severe clinical findings, two or more genes may be responsible and further investigation may be required. [ABSTRACT FROM AUTHOR]

Epilepsy, a neurological disorder characterized by recurrent seizures, manifests as a heterogeneous group of conditions, with genetic factors emerging as pivotal contributors to its pathogenesis. Various genes have been implicated in elevating susceptibility to epilepsy, offering crucial insights into the disorder's underlying mechanisms. These genes, influencing key aspects of brain function such as ion channel regulation, neurotransmitter release, and neuronal excitability, when mutated, disrupt the delicate balance of neuronal activity, culminating in abnormal electrical discharges and seizure manifestation. Genetic testing assumes a crucial role in the diagnostic process, facilitating the identification of causative mutations. As our comprehension of the genetic architecture of epilepsy evolves, genetic testing becomes increasingly integral in informing clinical decisionmaking. Treatment modalities for genetic epilepsy encompass a spectrum including antiepileptic drugs, ketogenic diets, and, in certain cases, surgical interventions. Ongoing research endeavors focus on unraveling intricate genetic interactions contributing to epilepsy, holding promise for novel therapeutic targets. Within the comprehensive management of epilepsy, genetic counseling provides indispensable information and support to affected individuals and their families. Precision medicine, leveraging unique genetic profiles, holds potential for more individualized treatment strategies. Advancements in gene-editing technologies further offer prospects for targeted correction of pathogenic mutations, introducing a potential curative dimension to the management of genetic epilepsy. In sum, the integration of genetic insights into diagnosis, treatment, and counseling underscores a transformative paradigm in addressing the complexities of epilepsy. [ABSTRACT FROM AUTHOR]

Recurrent pregnancy loss (RPL) is when a woman has three or more miscarriages in a row. Chromosomal abnormalities are frequently seen in RPL cases. In this case report, we detected a balanced t(2;7)(q31;p21) translocation in the male partner of a couple who applied to Erciyes University, Department of Medical Genetics with the indication of RPL. Balanced translocation is a type of chromosomal anomaly in which two chromosomes swap parts, but the total amount of genetic material remains the same. Balanced translocations are generally harmless to the carrier, but may increase the risk of RPL and other pregnancy complications. The female partner of the couple in this case had a normal karyotype (46,XX), but the male partner had a balanced translocation between chromosomes 2 and 7 (46,XY,t(2;7)(q31;p21)). For this reason, the couple's children were also examined in terms of family segregation. The t(2;7)(q31;p21) translocation is new to the literature and has not previously been reported as a cause of RPL. In our study, by performing Gene Ontology Enrichment Analysis, we determined that morbid genes in the relevant translocation regions are effective in embryo development. In the light of all the analyses, we conclude that the unbalanced transfer of the 46,XY,t(2;7)(q31;p21) karyotype to the next generation negatively affects the survival of the embryo due to the effect of morbid genes. [ABSTRACT FROM AUTHOR]

Introduction: The genetic risk factors for Coronavirus disease-2019 (COVID19)-associated pulmonary fibrosis (CAPF) are not clearly defined. Mutations in the genes encoding telomerase reverse transcriptase (TERT) and mucin 5B (MUC5B) are well-known genetic risk factors for pulmonary fibrosis. In this study, we aimed to show whether the most common proven mutations of pulmonary fibrosis affect the development of CAPF., Materials and Methods: Forty-eight patients who were matched for age, gender, COVID-19 disease severity, and respiratory support type and needed high flow nasal cannula, non-invasive mechanical ventilator, or invasive mechanical ventilator due to COVID-19 were followed up prospectively. Eighteen patients were excluded from the follow-up due to known structural lung disease, collagen tissue disease, and occupational exposure to fibrosis. The patients were called for follow-up three months after discharge, and CT was performed. Those with fibrosis (n= 15) in the third-month follow-up CT were included in the CAPF group, and those with complete resolution (n= 15) were included in the control group. Blood samples were taken for genetic analysis., Result: TERT gene study revealed that six (40%) of the fibrosis group was normal, while five were heterozygous (33.3%). MUC5B polymorphism was not detected in 10 (66.7%) of the fibrosis group., Conclusions: Individuals with TERT mutations may be at a higher risk for CAPF. Further studies are needed to clarify the genetic risk factors for CAPF.