Genetic Findings Research Articles

The value of age of onset and family history as predictors of molecular diagnosis in a Swedish cohort of inherited retinal disease.

This study aimed to characterize clinical and genetic findings in a Swedish cohort with inherited retinal disease (IRD), identify predictors for achieving a molecular diagnosis and evaluate the effects of increased genetic testing over time. Clinical and genetic data from 324 nonrelated IRD index individuals referred for genetic testing in the Stockholm region between 2016 and 2023 were collected retrospectively and analysed by clinical subtype, age of onset and testing period (2016-2020 vs. 2021-2023). Logistic regression was used to calculate odds ratios for age of onset and family history on the likelihood of achieving a molecular diagnosis. The diagnostic yield was 55% and involved 56 genes. In 10% of solved individuals, the molecular diagnosis refined the clinical diagnosis. For each 1-year increase in age of onset, the odds of achieving a molecular diagnosis decreased by 3% (odds ratio 0.97, 95% confidence interval 0.96-0.98). A positive family history doubled the odds (odds ratio 2.1, 95% confidence interval 1.3-3.4). The use of genetic testing increased 2.1-fold and the number of molecular diagnoses increased 1.6-fold relative to the population of the Stockholm region between the two testing periods. This study adds to the knowledge of the clinical and genetic landscape of IRDs in Sweden and establishes age of onset and family history as significant predictors for achieving a molecular diagnosis. Increased genetic testing on a population level substantially increased the number of individuals receiving a molecular diagnosis with a high diagnostic yield compared to other rare diseases.

Complications of the Bacillus Calmette-Guerin vaccine as an early warning sign of inborn errors of immunity: a report of 197 patients

BackgroundAccording to the WHO’s recommendation for developing countries, Bacillus Calmette-Guerin (BCG) vaccination has been implemented in some countries as part of national vaccination programs at birth. Although it is generally considered safe, some complications may occur; including BCGitis (local) or BCGosis (systemic), ranging from mild like local abscesses to fatal impediments like osteomyelitis and disseminated BCG infection. This study aimed to determine the spectrum of inborn errors of immunity (IEI) in BCG-vaccinated neonates experiencing local or systemic complications.MethodsIn this cross-sectional study, we investigated Iranian children referred to the Immunology, Asthma, and Allergy Research Institute (IAARI) between 2007-2023 for suspected immunodeficiency. Medical history was recorded, and primary screening tests for immunodeficiency were conducted for all cases. For suspected cases, more advanced immunologic investigations were performed to reach a definitive diagnosis. Furthermore, the study incorporated the documented genetic findings of the patients under investigation. All patients with inborn error of immunity who had a history of BCG vaccine complications within the first year of vaccination were enrolled in the study.ResultsWe investigated 3,275 cases suspected of IEI, identifying197 patients with both IEI and BCG vaccine complications. Among these, 127 (64.5%) were male. Symptoms began at or before 3 months of age in 64.8% of the cases, and parental consanguinity was reported in 79.2%. Genetic diagnoses were confirmed in 108 patients. Of the 197 patients, 108 (54.8%) had BCGitis, while 89 (45.2%) experienced systemic complications (BCGosis). A family history of IEI, BCG-related complications, and unexplained deaths were observed in 20.3%, 12.2%, and 29.9% of cases, respectively. Furthermore, 46.2% had at least one of these three risk factors in their history.ConclusionsEarly BCG vaccine complications may indicate an underlying immunodeficiency, particularly when there is a positive family history of BCG complications, immunodeficiency, or unexplained deaths. Nation-wide vaccination protocols should address this issue by delaying inoculation to allow for immunological screening of suspected immunodeficient patients, thereby preventing BCG vaccine-related morbidity and mortality.

Clinical and Genetic Findings in Patients With Palmoplantar Keratoderma

Palmoplantar keratoderma poses diagnostic challenges due to its clinical and genetic heterogeneity, and knowledge on the value of systematic genetic testing on clinically well-described patient cohorts is sparse. To improve knowledge of the clinical and genetic spectrum of patients with palmoplantar keratoderma. This cohort study prospectively recruited patients and affected family members with palmoplantar keratoderma between September 1, 2016, and December 31, 2022. Patients were recruited from private practitioners in dermatology and dermatology departments in Denmark. Study participants were patients 18 years or older either newly diagnosed with palmoplantar keratoderma or being followed up for the disease at referral centers. Phenotypes and clinical subtypes were classified. Genetic testing was performed by whole-exome or genome sequencing using an in silico panel containing genes related to palmoplantar keratoderma, or by Sanger sequencing for specific variants. Descriptive analysis, such as proportions and frequency, were used to describe clinical characteristics, distribution of disease-causing variants, and genotype-phenotype associations. This study included 142 study participants from 76 families (90 [63%] female; median [range] age, 52 [18-92] years). Clinical subtypes included 42 punctate (55%), 26 diffuse (34%), 5 focal (7%), and 3 striate (4%). A genetic diagnosis was found in 63 of 76 families (83%), including 27 disease-causing variants within 13 different genes: AAGAB (n = 39), DSG1 (n = 8), KRT1 (n = 3), DSP (n = 2), KRT9 (n = 2), AQP5 (n = 2), KRT16 (n = 1), SERPINA12 (n = 1), ABCA12 (n = 1), COL7A1 (n = 1), CARD14 (n = 1), DST (n = 1), and LORICRIN (n = 1). All participants with AAGAB variants presented with punctate palmoplantar keratoderma, showing a clear genotype-phenotype correlation. The other subtypes (diffuse, focal, and striate) proved more challenging to clinically subclassify, and disease-causing variants were identified in 12 genes, contributing to more complex genotype-phenotype patterns. Patients with palmoplantar keratoderma due to DSP variants were found, which is important to identify because of an associated risk of cardiomyopathy. This study provides novel insights into the clinical and genetic spectrum of patients with palmoplantar keratoderma. It demonstrates the value of genetic testing for accurate diagnoses and to distinguish between different subtypes. The established and well-described cohort lays the foundation for future research in palmoplantar keratoderma.

Using red–green–blue vegetation indices to evaluate complex agronomical traits in soybean breeding

AbstractHigh‐throughput phenotyping is an emerging tool that allows access to identify simple and complex traits, accelerating genetic discoveries and selection. Vegetation indices strongly correlate with several economic crop traits, allowing plant breeders to detect variation in breeding populations. Thus, this study used red–green–blue (RGB) vegetation indices to evaluate the influence of the stink bug complex (Euschistus heros, Piezodorus guildinii, Nezara viridula, Dichelops melacanthus, and Edessa meditabunda) on the agronomical traits of soybean (Glycine max) lineages. For instance, two experiments were conducted to assess soybean resistance to the stink bug complex, (1) with and (2) without pesticide control. An unmanned aerial vehicle coupled with an RGB camera acquired aerial photography over the field during the R5 stage. Four vegetation indices and canopy were estimated from the orthomosaic, and the genotypes were evaluated based on agronomical traits. Linear mixed models were used to estimate the variance and significance test of each trait using the likelihood ratio test, and the principal component analysis was performed to verify the multivariate pattern among genotypes. The results showed significant genotypic effects for most traits with high broad‐sense heritability for agronomical traits and moderate for vegetation indices. Significant correlations using best linear unbiased predictions were observed among the agronomical traits with the vegetation indices and canopy coverage, which can be used as a tool for the indirect selection of soybean lineages in the breeding pipeline.

Genetic Discovery and Risk Prediction for Type 1 Diabetes in Individuals Without High-Risk HLA-DR3/DR4 Haplotypes.

More than 10% of patients with type 1 diabetes (T1D) do not have high-risk HLA-DR3 or -DR4 haplotypes with distinct clinical features, such as later onset and reduced insulin dependence. We aimed to identify genetic drivers of T1D in the absence of DR3/DR4 and improve prediction of T1D risk in these individuals. We performed T1D association and fine-mapping analyses in 12,316 non-DR3/DR4 samples. Next, we performed heterogeneity tests to examine differences in T1D risk variants in individuals without versus those with DR3/DR4 haplotypes. We further assessed genome-wide differences in gene regulatory element and biological pathway enrichments between the non-DR3/DR4 and DR3/DR4 cohorts. Finally, we developed a genetic risk score (GRS) to predict T1D in individuals without DR3/DR4 and compared with an existing T1D GRS. A total of 18 T1D risk variants in non-DR3/DR4 samples were identified. Risk variants at the MHC and multiple other loci genome wide had heterogeneity in effects on T1D dependent on DR3/DR4 status, and non-DR3/DR4 T1D had evidence for a greater polygenic burden. T1D-assocated variants in non-DR3/DR4 were more enriched for regulatory elements and pathways involved in antigen presentation, innate immunity, and β-cells and depleted in T cells compared with DR3/DR4. A non-DR3/DR4 GRS outperformed an existing risk score GRS2 in discriminating non-DR3/DR4 T1D from no diabetes (area under the curve 0.867; P = 7.48 × 10-32) and type 2 diabetes (0.907; P = 4.94 × 10-44). In total, we identified heterogeneity in T1D genetic risk dependent on high-risk HLA-DR3/DR4 haplotype, which uncovers disease mechanisms and enables more accurate prediction of T1D across the HLA background.

Clinical Actionability of Genetic Findings in Cerebral Palsy

Single gene variants can cause cerebral palsy (CP) phenotypes, yet the impact of genetic diagnosis on CP clinical management has not been systematically evaluated. To evaluate how frequently genetic testing results would prompt changes in care for individuals with CP and the clinical utility of precision medicine therapies. Published pathogenic or likely pathogenic variants in OMIM genes identified with exome sequencing in clinical (n = 1345) or research (n = 496) cohorts of CP were analyzed. A systematic literature review for evidence of effective therapies for specific genetic etiologies was performed. Nonstandard interventions that led to a detectable improvement in a defined outcome in individuals with variants in the gene of interest were included. Literature was evaluated using PRISMA guidelines. A diverse, expert working group was established, scoring rubrics adapted, and scoring consensus built with a modified Delphi approach. Overall clinical utility was calculated from metrics assessing outcome severity if left untreated, safety and practicality of the intervention, and anticipated intervention efficacy on a scale from 0 to 3. Of 1841 patients with CP who underwent exome sequencing, 502 (27%) had pathogenic or likely pathogenic variants related to their phenotype. A total of 243 different genes were identified. In 1841 patients with identified genetic etiologies of CP, 140 (8%) had a genetic etiology classified as actionable, defined as prompting a change in clinical management. Also identified were 58 of 243 genes with pathogenic or likely pathogenic variants with actionable treatment options: 16 targeting the primary disease mechanism, 16 with specific prevention strategies, and 26 with specific symptom management. The level of evidence was also graded according to ClinGen criteria; 45 of 101 interventions (44.6%) had evidence class D or below. The potential interventions have clinical utility with 98 of 101 outcomes (97%) being moderate-high severity if left untreated and 63 of 101 interventions (62%) predicted to be of moderate-high efficacy. Most interventions (72 of 101 [71%]) were considered moderate-high safety and practicality. The findings indicate that actionable genetic findings occurred in 8% of individuals referred for genetic testing with CP. Evaluation of potential efficacy, outcome severity, and intervention safety and practicality indicates moderate-high clinical utility of these genetic findings. Genetic sequencing can identify precision medicine interventions that provide clinical benefit to individuals with CP. The relatively limited evidence base underscores the need for additional research.

Zebrafish: A Genetic Wonder Revealing Regeneration and Drug Discovery Secrets

Zebrafish: A Genetic Wonder Revealing Regeneration and Drug Discovery Secrets

When Horse Became Steed: Archaeological and genetic discoveries topple long-standing ideas about the domestication of equines.

When Horse Became Steed: Archaeological and genetic discoveries topple long-standing ideas about the domestication of equines.

Advancing Gene Discovery for Substance Use Disorders Using Additional Traits Related to Behavioral Disinhibition.

Substance use disorders (SUDs) frequently co-occur with each other and with other traits related to behavioral disinhibition, a spectrum of outcomes referred to as externalizing. Nevertheless, genome-wide association studies (GWAS) typically study individual SUDs separately. This single-disorder approach ignores genetic covariance between SUDs and other traits and may contribute to the relatively limited genetic discoveries to date. To identify the most effective model for capturing genetic relationships between SUDs and externalizing phenotypes, optimizing the detection of genetic influences on SUDs while maintaining specificity. We used Genomic SEM to estimate SNP effects on a broad factor representing liability to externalizing and SUDs, on factors representing liability to behavioral disinhibition and SUDs separately, and on residualized SUDs. Subsequent gene-based, tissue expression, and polygenic score (PGS) analyses were used to compare the ability of these alternative approaches to identify genetic influences on SUDs. This study was carried out from May 2023 - September 2024. We used GWAS summary statistics based on samples of European ancestry from previous studies of externalizing and SUD phenotypes in the main multivariate GWAS ( N > 2.2 million). We used two independent samples to estimate polygenic associations, a family-based sample enriched for substance use problems (COGA; N = 7,530) and a population-based sample representative of the United States, (All of Us; N = 77,442). N/A. Across the three factors (Externalizing; SUDs; Behavioral Disinhibition) and four residualized SUDs (alcohol, tobacco, opioid, and cannabis), we compared the number, putative function, previous associations of significant genomic risk loci and genes, and variance explained by polygenic scores in substance use outcomes. We identified genomic risk loci and genes uniquely associated with Externalizing that are relevant to the neurobiology of substance use. Genes identified for residual SUDs were involved in substance-specific processes (e.g., metabolism). The Externalizing PGS accounted for the most variance in substance outcomes relative to the PGS for the other factors and residual PGS appeared to capture substance specific signals. Our findings suggest that modeling both a broad genetic liability to externalizing behaviors and substance-specific liabilities enhances the detection of genetic effects related to SUDs and explains more variance in substance use outcomes. Question: Can we advance gene discovery for substance use disorders (SUDs) by incorporating information about correlated outcomes related to behavioral disinhibition?Findings: Combining genetic effects common to SUDs and behavioral disinhibition in a multivariate genome-wide association study of > 2.2 million individuals identified 708 genomic risk loci and accounted for more variance in SUD phenotypes compared with modeling each set of phenotypes separately.Meaning: SUDs and behavioral dysregulation are influenced by a common set of common variants; modeling their joint contributions improves power for genetic discovery and polygenic prediction.

Multimodal analysis of RNA sequencing data powers discovery of complex trait genetics

RNA sequencing has the potential to reveal many modalities of transcriptional regulation, such as various splicing phenotypes, but studies on gene regulation are often limited to gene expression due to the complexity of extracting and analyzing multiple RNA phenotypes. Here, we present Pantry, a framework to efficiently generate diverse RNA phenotypes from RNA sequencing data and perform downstream integrative analyses with genetic data. Pantry generates phenotypes from six modalities of transcriptional regulation (gene expression, isoform ratios, splice junction usage, alternative TSS/polyA usage, and RNA stability) and integrates them with genetic data via QTL mapping, TWAS, and colocalization testing. We apply Pantry to Geuvadis and GTEx data, finding that 4768 of the genes with no identified eQTL in Geuvadis have QTL in at least one other transcriptional modality, resulting in a 66% increase in genes over eQTL mapping. We further found that the QTL exhibit modality-specific functional properties that are further reinforced by joint analysis of different RNA modalities. We also show that generalizing TWAS to multiple RNA modalities approximately doubles the discovery of unique gene-trait associations, and enhances identification of regulatory mechanisms underlying GWAS signal in 42% of previously associated gene-trait pairs.

Construction of a high-density genetic map and QTL mapping of growth traits in kiwifruit

The trunk diameter (TD) and annual branch diameter (ABD) are closely associated with the growth vigor, abiotic resistance and fruit yield of kiwifruit. These traits are quantitative traits that are controlled by more than one quantitative trait loci (QTLs). However, QTLs for TD and ABD in kiwifruit remain unelucidated. In this study, we generated a cross of the diploid species Actinidia chinensis ‘Hongyang’ (♀) × ‘Boshanbiyu’ (♂) and performed restriction-site associated DNA sequencing on the parents and 173 F1 progeny to identify single-nucleotide polymorphisms (SNPs) in the population. A high-density linkage map spanning 2,548.97 cM was developed using 6,506 bin markers. This bin map consisted of 29 linkage group (LG), with an average genetic distance of 0.39 cM. A total of 8 QTLs were identified: four for TD and four for ABD, with the variance explained by these QTLs ranging from 4.43 % to 16.11 %. A total of 358 TD genes and 181 ABD genes were extracted from the mapped QTLs, and analyzed by KEGG enrichment. In addition, we developed a TD marker from LG23 and an ABD marker from LG10 which were significantly correlated with growth traits. The TD marker is associated with Actinidia22292, a gene involved in protein polar localization, while the ABD marker is linked to Actinidia40478, an Ein3-binding F-box protein. The two SNP markers developed in this study were further validated in a biparental population, indicating their potential use in predicting seedling growth vigor. In summary, these genetic findings deepen our understanding of the genetic basis of growth traits in kiwifruit, and provide valuable information to facilitate kiwifruit breeding.

Genetically confirmed Charcot–Marie–Tooth disease type 2A manifesting with postural tremor: a case report

BackgroundCharcot–Marie–Tooth disease is a spectrum of inherited disorders characterized by both motor and sensory manifestations, which include prominent distal muscle weakness, foot deformities (pes cavus and hammer toes), and sensory deficits. Postural tremor as a manifestation of Charcot–Marie–Tooth is seldom present, except in a variant of Charcot–Marie–Tooth subtype 1 (Roussy–Levy syndrome), and its presence often results in a diagnostic dilemma.Case presentationWe present a 34-year-old Eritrean man who came to our hospital with a complaint of tremors of the hands of 6 months duration. Associated with this, he had difficulty walking and weakness of the distal extremities bilaterally, prominently involving the lower limbs. The patient denied a family history of such illness. Physical examination revealed distal muscle weakness (4+/5 on upper limbs, while 3/5 on lower limbs bilaterally), pes cavus deformity, absent ankle reflexes, and mild vibratory sensory loss. We noted a postural tremor that attenuated when the patient assumed an anatomic position. The tremor was limited to the hands. Nerve conduction study of upper and lower limbs showed moderate to severe motor axonal and demyelinating polyneuropathy (axonal > demyelinating), suggestive of mixed axonal and demyelinating hereditary polyneuropathy. Subsequently, genetic testing revealed copy number changes (heterozygous deletion) on the MPZ and MFN2, while the PMP22 gene showed ambiguous copy number changes (decrease) on exons 2 and 3. Tying the clinical, electrophysiologic, and genetic findings, consideration of Charcot–Marie–Tooth subtype 2A with postural tremor was made. Subsequently, the patient was managed with regular physiotherapy and an anxiolytic resulting in minimal symptom improvement.ConclusionThe present case describes a 34-year-old male patient with Charcot–Marie–Tooth subtype 2A presenting with neuropathic postural tremor, which is a rare presentation of a common hereditary polyneuropathy. This case highlights the fact that tremors can be associated with peripheral neuropathy syndromes, and a high index of suspicion is needed to rightly diagnose our patients.

Twenty-first century mouse genetics is again at an inflection point.

The laboratory mouse has been the premier model organism for biomedical research owing to the availability of multiple well-characterized inbred strains, its mammalian physiology and its homozygous genome, and because experiments can be performed under conditions that control environmental variables. Moreover, its genome can be genetically modified to assess the impact of allelic variation on phenotype. Mouse models have been used to discover or test many therapies that are commonly used today. Mouse genetic discoveries are often made using genome-wide association study methods that compare allelic differences in panels of inbred mouse strains with their phenotypic responses. Here we examine changes in the methods used to analyze mouse genetic models of biomedical traits during the twenty-first century. To do this, we first examine where mouse genetics was before the first inflection point, which was just before the revolution in genome sequencing that occurred 20 years ago, and then describe the factors that have accelerated the pace of mouse genetic discovery. We focus on mouse genetic studies that have generated findings that either were translated to humans or could impact clinical medicine or drug development. We next explore how advances in computational capabilities and in DNA sequencing methodology during the past 20 years could enhance the ability of mouse genetics to produce solutions for twenty-first century public-health problems.

Targeted medical therapies for vascular anomalies.

The last 2 decades of genetic discovery in the field of vascular anomalies have brought targeted medical therapies to the forefront of care patients with vascular anomalies and have broadened the role of hematologists/oncologists in this field. Many vascular anomalies have now been identified to be driven by somatic gain-of-function variants in the PI3K/AKT/ mTOR and Ras/MAPK intracellular signaling pathways. This has led to the introduction of various antiangiogenic agents that inhibit these pathways. Knowledge of the indications for and the safe administration of these agents in patients with vascular anomalies is now a crucial part of training for hematologists/oncologists.

A multi-ancestry genome-wide association study identifies novel candidate loci in the RARB gene associated with hypertensive disorders of pregnancy

Genetic factors related to pregnancy-related traits are understudied, especially in ancestrally diverse cohorts. To assess maternal contributions to hypertensive disorders of pregnancy (HDP, we performed a multi-ancestry genome-wide association study (GWAS) of HDP in data from the North Carolina-based Personalized Environment and Genes Study (PEGS) cohort with validation in the UK Biobank (UKBB). The GWAS revealed two maternal loci associated with HDP at the genome-wide significance level. The lead independent variants were rs114954125 on chromosome 2 (near LRP1B; OR (95% CI): 2.96 (2.02,4.34); P=2.82 x 10-8) and rs61176331 on chromosome 3 (on RARB; OR (95% CI): 3.08 (2.12,4.48); P=3.52 x 10-9). We validated the associations near RARB with a meta-analysis of PEGS and the UK Biobank. We also identified cis-eQTLs in the candidate region associated with decreased RARB expression in macrophage cells exposed to Salmonella. Chromatin mapping in FUMA identified a significant interaction within chromosome 3's enhancer and open chromatin regions, with strong effects observed for RARB and H3P10 gene regulation in mesendoderm cells, mesenchymal stem cells, and trophoblast-like stem cells. We applied existing polygenic scores (PGS) for preeclampsia and gestational hypertension and found the scores were significantly associated with HDP in PEGS. The findings demonstrate the power of multi-ancestry studies for genetic discovery and highlight the relationship between immune response, regulation, and HDP and the utility of PGS for risk prediction.

Mutations in unfolded protein response regulator ATF6 cause hearing and vision loss syndrome.

Activating transcription factor 6 (Atf6) is a key regulator of the unfolded protein response (UPR) and is important for endoplasmic reticulum (ER) function and protein homeostasis in metazoan cells. Patients carrying loss-of-function ATF6 disease alleles develop the cone dysfunction disorder, achromatopsia. The impact of loss of ATF6 function on other cell types, organs, and diseases in people remains unclear. Here, we reported that progressive sensorineural hearing loss was a notable complaint in some patients carrying ATF6 disease alleles and that Atf6-/- mice also showed progressive auditory deficits affecting both genders. In mice with hearing deficits, we found disorganized stereocilia on hair cells and focal loss of outer hair cells. Transcriptomic analysis of Atf6-/- cochleae revealed marked induction of UPR, especially through the PERK arm. These findings identify ATF6 as an essential regulator of cochlear health and function. Furthermore, they supported that ATF6 inactivation in people causes progressive sensorineural hearing loss as part of a blindness-deafness genetic syndrome targeting hair cells and cone photoreceptors. Lastly, our genetic findings support ER stress as an important pathomechanism underlying cochlear damage and hearing loss with clinical implications for patient lifestyle modifications that minimize environmental/physiologic sources of ER stress to the ear.

Dystrophinopathy patient data as a guide to interpretation of pregestational female population screening for DMD gene variants.

Pregestational population screening of healthy females for copy number variants in DMD gene has raised numerous challenges regarding the interpretation and disclosure of these findings. Our objective was to analyze data from a local dystrophinopathy patient database, in comparison to population screening results. Utilizing the "Little steps" association registry for children with dystrophinopathy, we classified genetic findings (out-of-frame, in-frame, or difficult-to-predict) in 231 DMD and 90 BMD male patients. A comparison was made with a previously published cohort of 162 female carriers identified through population screening. Duplications classified as "difficult to predict" were absent in DMD/BMD patients, as opposed to 45.1% of women analyzed in the scope of population screening (p < 0.0001). While the distribution of deletions did not differ between the groups, significantly higher proportion of duplications initiated at the proximal hot spot in the DMD/BMD cohort (87.1%), vs. only 11.7% in women analyzed through population screening (p = 0.0038). Notably, duplications initiating in the dp427c promoter area were noted only in the latter cohort (n = 62). Local databases of dystrophinopathy patients can facilitate analysis and reporting of pregestational female population screening results. These conclusions facilitate future introductions of population screening genetic tests for diseases with variable presentation.

Review of structural neuroimaging and genetic findings in autism spectrum disorder- a clinical perspective.

Autism spectrum disorders (ASDs) are neurodevelopmental conditions characterized by deficits in social relationships and communication and restrictive, repetitive behaviors and interests. ASDs form a heterogeneous group from a clinical and genetic perspective. Currently, ASDs diagnosis is based on the clinical observation of the individual's behavior. The subjective nature of behavioral diagnoses, in the context of ASDs heterogeneity, contributes tosignificant variation in the age at ASD diagnosis. Early detection has been proved to be critical in ASDs, as early start of appropriate therapeutic interventions greatly improve the outcome for some children. Structural magnetic resonance imaging (MRI) is widely used in the diagnostic work-up of neurodevelopmental conditions, including ASDs, mostly for brain malformations detection. Recently, the focus of brain imaging shifted towards quantitative MRI parameters, aiming to identify subtle changes that may establish early detection biomarkers. ASDs have a strong genetic component; deletions and duplications of several genomic loci have been strongly associated with ASDs risk. Consequently, a multitude of neuroimaging and genetic findings emerged in ASDs in the recent years. The association of gross or subtle changes in brain morphometry and volumes with different genetic defects has the potential to bring new insights regarding normal development and pathomechanisms of various disorders affecting the brain. Still, the clinical implications of these discoveries and the impact of genetic abnormalities on brain structure and function are unclear. Here we review the literature on brain imaging correlated with the most prevalent genomic imbalances in ASD, and discuss the potential clinical impact.

Exosc10 deficiency in the initial segment is dispensable for sperm maturation and male fertility in mice

Summary EXOSC10 is an exosome-associated ribonuclease that degrades and processes a wide range of transcripts in the nucleus. The initial segment (IS) of the epididymis is crucial for sperm transport and maturation in mice by affecting the absorption and secretion that is required for male fertility. However, the role of EXOSC10 ribonuclease-mediated RNA metabolism within the IS in the regulation of gene expression and sperm maturation remains unknown. Herein, we established an Exosc10 conditional knockout (Exosc10 cKO) mouse model by crossing Exosc10 F/F mice with Lcn9-Cre mice which expressed recombinase in the principal cells of IS as early as post-natal day 17. Morphological and histological analyses revealed that Exosc10 cKO males had normal spermatogenesis and development of IS. Moreover, the sperm concentration, morphology, motility, and frequency of acrosome reactions in the cauda epididymides of Exosc10 cKO mice were comparable with those of control mice. Thus, Exosc10 cKO males had normal fertility. Collectively, our genetic mouse model and findings demonstrate that loss of EXOSC10 in the IS of epididymis is dispensable for sperm maturation and male fertility.

Expanding the genotypic and phenotypic spectrum of Egyptian children with maple syrup urine disease

Maple Syrup Urine Disease (MSUD, OMIM# 248600) is an autosomal recessive inborn error of metabolism characterized by elevated branched chain amino acids (BCAA) leucine/isoleucine and valine in blood of affected children. The phenotypic and genotypic spectrum of MSUD is largely unreported in Egypt. We recruited ten patients (4 males/6 females, 2weeks-12years) from nine unrelated families with clinical and biochemical evidence of MSUD. We performed Sanger sequencing for the three most-commonly responsible genes: BCKDHA, BCKDHB and DBT and conducted exome sequencing for unresolved cases. Through Sanger sequencing, we detected eight homozygous pathogenic/likely pathogenic variants (four in BCKDHB, three in BCKDHA and one in DBT gene) in eight different families. The proband of family VI, who had no significant genetic findings by Sanger, had a peculiar phenotype and atypical radiological findings. His exome sequencing revealed a previously reported homozygous likely pathogenic variant in the RARS2 gene (NM_020320.5:c.1026G > A;p.(Met342Ile)) causing the mitochondrial-encephalopathy disorder pontocerebellar hypoplasia, type 6 (OMIM# 611523). Furthermore, the copy-number-variant analysis of the exome data revealed a biallelic duplication affecting exons 2–6 of the BCKDHB gene (GRCh38: Chr.6-g.80127496:80171441dup) evaluated as variant of uncertain significance but expected to cause a breakpoint and may disrupt gene function, which can explain the markedly elevated BCAA levels in the patient’s blood. In conclusion, we expanded the genotypic and phenotypic spectrum of the disease and showed that aggressive intervention with specific treatment in the first few days of life resulted in normal development even in a developing country setting. Inclusion of MSUD in the national newborn screening program in Egypt is highly recommended.