Cerebellar impairments in genetic models of autism spectrum disorders: A neurobiological perspective.

Functional and molecular alterations in the cerebellum are among the most widely recognised associates of autism spectrum disorders (ASD). As a critical computational hub of the brain, the cerebellum controls and coordinates a range of motor, affective and cognitive processes. Despite well-described circuits and integrative mechanisms, specific changes that underlie cerebellar impairments in ASD remain elusive.

Pathogenic SCN2A variants cause early-stage dysfunction in patient-derived neurons.

Pathogenic heterozygous variants in SCN2A, which encodes the neuronal sodium channel NaV1.2, cause different types of epilepsy or intellectual disability (ID)/autism without seizures. Previous studies using mouse models or heterologous systems suggest that NaV1.

Generation and characterization of an endogenously tagged SPG11-human iPSC line by CRISPR/Cas9 mediated knock-in.

Pathogenic bi-allelic variants in the SPG11 gene result in rare motor neuron disorders such as Hereditary Spastic Paraplegia type 11, Charcot-Marie Tooth, and Juvenile Amyotrophic Lateral Sclerosis-5. The main challenge in SPG11-linked disease research is the lack of antibodies against SPG11 encoded spatacsin. Here, we describe the CRISPR/Cas9 mediated generation and validation of an endogenously tagged SPG11- human iPSC line that contains an HA tag at the C-terminus of SPG11.

Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior.

Purpose: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis.

Methods: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7.

New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics.

Purpose: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority.

Methods: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants.

Severe reaction to radiotherapy provoked by hypomorphic germline mutations in ATM (ataxia-telangiectasia mutated gene).

Background: A minority of breast cancer (BC) patients suffer from severe reaction to adjuvant radiotherapy (RT). Although deficient DNA double-strand break repair is considered the main basis for the reactions, pretreatment identification of high-risk patients has been challenging.

Methods: To retrospectively determine the etiology of severe local reaction to RT in a 39-year-old woman with BC, we performed next-generation sequencing followed by further clinical and functional studies.

Applying Rogers' framework to evaluate public awareness and knowledge of medical genetics in a developing country.

Public knowledge of medical genetics is essential for better establishment of its services but has been rarely evaluated based on distinguished types of knowledge. We designed and validated a new self-administered questionnaire in Farsi (Persian language) to assess public knowledge of medical genetics based on Rogers' framework. This framework divides knowledge into three types of awareness, how-to (practical) and principles knowledge which refer to knowing the existence, proper use, and theoretical principles of an innovation, respectively.

Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly.

Purpose: Microcephaly is a sign of many genetic conditions but has been rarely systematically evaluated. We therefore comprehensively studied the clinical and genetic landscape of an unselected cohort of patients with microcephaly.

Methods: We performed clinical assessment, high-resolution chromosomal microarray analysis, exome sequencing, and functional studies in 62 patients (58% with primary microcephaly [PM], 27% with secondary microcephaly [SM], and 15% of unknown onset).

Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes.

Background: Deleterious variants in the voltage-gated sodium channel type 2 (Na1.2) lead to a broad spectrum of phenotypes ranging from benign familial neonatal-infantile epilepsy (BFNIE), severe developmental and epileptic encephalopathy (DEE) and intellectual disability (ID) to autism spectrum disorders (ASD). Yet, the underlying mechanisms are still incompletely understood.

The role of recessive inheritance in early-onset epileptic encephalopathies: a combined whole-exome sequencing and copy number study.

Early-onset epileptic encephalopathy (EE) and combined developmental and epileptic encephalopathies (DEE) are clinically and genetically heterogeneous severely devastating conditions. Recent studies emphasized de novo variants as major underlying cause suggesting a generally low-recurrence risk. In order to better understand the full genetic landscape of EE and DEE, we performed high-resolution chromosomal microarray analysis in combination with whole-exome sequencing in 63 deeply phenotyped independent patients.

Need for high-resolution Genetic Analysis in iPSC: Results and Lessons from the ForIPS Consortium.

Genetic integrity of induced pluripotent stem cells (iPSCs) is essential for their validity as disease models and for potential therapeutic use. We describe the comprehensive analysis in the ForIPS consortium: an iPSC collection from donors with neurological diseases and healthy controls. Characterization included pluripotency confirmation, fingerprinting, conventional and molecular karyotyping in all lines.

De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder.

Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11.

Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling.

Acrocallosal syndrome (ACLS) is an autosomal recessive neurodevelopmental disorder caused by KIF7 defects and belongs to the heterogeneous group of ciliopathies related to Joubert syndrome (JBTS). While ACLS is characterized by macrocephaly, prominent forehead, depressed nasal bridge, and hypertelorism, facial dysmorphism has not been emphasized in JBTS cohorts with molecular diagnosis. To evaluate the specificity and etiology of ACLS craniofacial features, we performed whole exome or targeted Sanger sequencing in patients with the aforementioned overlapping craniofacial appearance but variable additional ciliopathy features followed by functional studies.

Genotype-phenotype evaluation of MED13L defects in the light of a novel truncating and a recurrent missense mutation.

A decade after the designation of MED13L as a gene and its link to intellectual disability (ID) and dextro-looped transposition of great arteries in 2003, we previously described a recognizable syndrome due to MED13L haploinsufficiency. Subsequent reports of 22 further patients diagnosed by genome-wide testing further delineated the syndrome with expansion of the phenotypic spectrum and showed reduced penetrance for congenital heart defects. We now report two novel patients identified by whole exome sequencing, one with a de novo MED13L truncating mutation and the other with a de novo missense mutation.

Perfluorocarbon attenuates inflammatory cytokines, oxidative stress and histopathologic changes in paraquat-induced acute lung injury in rats.

The effects of perfluorocarbon (PFC) on paraquat (PQ) induced acute lung injury (ALI) was evaluated among rats. Twenty four Wistar rats were divided into 4 groups: control group injected by saline physiologic 0.9%, PFC group injected by Perfluorocarbon, PQ group injected by PQ and PQ+PFC group injected by PFC one hour after receiving paraquat.

The clinical significance of small copy number variants in neurodevelopmental disorders.

Background: Despite abundant evidence for pathogenicity of large copy number variants (CNVs) in neurodevelopmental disorders (NDDs), the individual significance of genome-wide rare CNVs <500 kb has not been well elucidated in a clinical context.

Methods: By high-resolution chromosomal microarray analysis, we investigated the clinical significance of all rare non-polymorphic exonic CNVs sizing 1-500 kb in a cohort of 714 patients with undiagnosed NDDs.

Results: We detected 96 rare CNVs <500 kb affecting coding regions, of which 58 (60.

High-resolution chromosomal microarrays in prenatal diagnosis significantly increase diagnostic power.

Objective: The objective of this study was to determine for the first time the reliability and the diagnostic power of high-resolution microarray testing in routine prenatal diagnostics.

Methods: We applied high-resolution chromosomal microarray testing in 464 cytogenetically normal prenatal samples with any indication for invasive testing.

Results: High-resolution testing revealed a diagnostic yield of 6.

Correlation of Body Mass Index and Serum Parameters With Ultrasonographic Grade of Fatty Change in Non-alcoholic Fatty Liver Disease.

Background: Non-alcoholic fatty liver disease (NAFLD) is a common liver disease in the western population and expanding disease in the world. Pathological changes in fatty liver are like alcohol liver damage, which can lead to end-stage liver disease. The prevalence of NAFLD in obese or overweight people is higher than general population, and it seems that people with high Body Mass Index (BMI) or abnormality in some laboratory tests are more susceptible for severe fatty liver and high grade of NAFLD in ultrasonography (U.

Inspirations in medical genetics.

There are abundant instances in the history of genetics and medical genetics to illustrate how curiosity, charisma of mentors, nature, art, the saving of lives and many other matters have inspired great discoveries. These achievements from deciphering genetic concepts to characterizing genetic disorders have been crucial for management of the patients. There remains, however, a long pathway ahead.

Further delineation of genotype-phenotype correlation in homozygous 2p21 deletion syndromes: first description of patients without cystinuria.

Homozygous contiguous gene deletion syndromes are rare. On 2p21, however, several overlapping homozygous gene deletion syndromes have been described, all presenting with cystinuria but otherwise distinct phenotypes. Hypotonia-cystinuria syndrome (HCS, OMIM606407) is characterized by infantile hypotonia, poor feeding, and growth hormone deficiency.

Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability.

A chromosomal balanced translocation disrupting the MED13L (Mediator complex subunit13-like) gene, encoding a subunit of the Mediator complex, was previously associated with transposition of the great arteries (TGA) and intellectual disability (ID), and led to the identification of missense mutations in three patients with isolated TGA. Recently, a homozygous missense mutation in MED13L was found in two siblings with non-syndromic ID from a consanguineous family. Here, we describe for the first time, three patients with copy number changes affecting MED13L and delineate a recognizable MED13L haploinsufficiency syndrome.

Anxiety, depression and health-related quality of life in those injured by landmines, Ilam, Islamic Republic of Iran.

We assessed depression, anxiety and health-related quality of life (HRQOL) in 137 cases of landmine injury in Ilam province, using the Hospital Anxiety & Depression Scale (HADS) and the Short Form Health Survey (SF36) questionnaires. We also compared their scores with an uninjured control group (n = 360). Most of the injured were male (93.