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Left ventricular septal myotomy provides a favorable prognosis for children with hypertrophic obstructive cardiomyopathy (HOCM). However, some children still suffer from recurrent left ventricular outflow tract obstruction (LVOTO) after surgery. Poor prognosis exists for HOCM caused by PTPN11 mutation. Therefore, the aim of this study was to determine the clinical features of recurrent obstruction in children with HOCM caused by pathogenic mutations in the PTPN11 gene. Fifty-six children who were diagnosed with HOCM underwent septal myectomies. Whole-exome sequencing of 49 pediatric cardiomyopathy–associated genes (including PTPN11) was performed. We performed hematoxylin-eosin, Masson, and wheat germ agglutinin staining of those tissues positive and negative for PTPN11. Whole-exome sequencing results showed 11 children with the PTPN11 mutation (19.6%). In long-term follow-up (median 37 months, maximum 9 years), children with the PTPN11 mutation had 6 (54.5%) recurrent LVOTOs compared with other groups (P =.015) but similar survival rates (P =.514). The mean postoperative time to recurrent obstruction was 22 ± 7 months. Children with PTPN11 mutation were 9-fold more likely to experience the risk associated with recurrent obstruction (95% confidence interval, 1.77-45.81, P <.001). Hematoxylin-eosin, Masson, and wheat germ agglutinin staining also revealed more cardiomyocyte hypertrophy in tissues with the PTPN11 mutation. Children with PTPN11 mutation–associated hypertrophic cardiomyopathy have a greater risk of recurrent LVOTO. [Display omitted] [ABSTRACT FROM AUTHOR]

Differences in interspecific mating traits, such as male sexual signals and female preferences, often evolve quickly as initial barriers to gene flow between nascent lineages, and they may also strengthen such barriers during secondary contact via reinforcement. However, it is an open question whether loci contributing to intraspecific variation in sexual traits are co-opted during the formation and strengthening of mating barriers between species. To test this, we used a population genomics approach in natural populations of Australian cricket sister species that overlap in a contact zone: Teleogryllus oceanicus and Teleogryllus commodus. First, we identified loci associated with intraspecific variation in T. oceanicus mating signals: advertisement song and cuticular hydrocarbon (CHC) pheromones. We then separately identified candidate interspecific barrier loci between the species. Genes showing elevated allelic divergence between species were enriched for neurological functions, indicating potential behavioral rewiring. Only two CHC-associated genes overlapped with these interspecific candidate barrier loci, and intraspecific CHC loci showed signatures of being under strong selective constraints between species. In contrast, 10 intraspecific song-associated genes showed high genetic differentiation between T. commodus and T. oceanicus , and 2 had signals of high genomic divergence. The overall lack of shared loci in intra vs. interspecific comparisons of mating trait and candidate barrier loci is consistent with limited co-option of the genetic architecture of interspecific mating signals during the establishment and maintenance of reproductive isolation. [ABSTRACT FROM AUTHOR]

ABSTRACT To investigate the clinical features and mutational spectrum underlying hypertrophic cardiomyopathy (HCM) in São Miguel Island (Azores, Portugal), we analyzed 37 adult patients (12 sporadic, 25 familial) with positive genetic tests. Seven disease‐causing variants were identified, being two novels, in three sarcomeric genes (MYH7, TNNT2, and MYBPC3) and one non‐sarcomeric gene (ALPK3). The novel variants, classified as likely pathogenic (LP), involved large multi‐exon deletions in MYBPC3 (exons 26–32 and 28–33). These deletions were found in heterozygosity in two young males who remained clinically stable, though early onset may predict a more severe prognosis. Segregation analysis in a consanguineous family revealed two new genotypes: a digenic heterozygous for MYH7:c.1750G>C (p.Gly584Arg; P) and TNNT2:c.842A>T (p.Asn281Ile; LP) variants, and a homozygous for the TNNT2 variant. The 70‐year‐old homozygous patient remained stable and without arrhythmic events, challenging the belief that homozygous variants have a worse prognosis. This study is the first molecular and clinical analysis of HCM in the Azores. [ABSTRACT FROM AUTHOR]

Understanding the processes that link genotype to phenotype is a central challenge in biology. Despite progress in discovering genes associated with ecologically relevant traits, a poor understanding of the processes and functions via which molecules mediate evolutionary differences leaves us critically far from linking proximate and ultimate causes of evolution. This knowledge gap is particularly large in multifaceted phenotypes of ecological relevance such as life histories where multiple traits covary and influence fitness. In Atlantic salmon (Salmo salar), variation in a key life-history trait, maturation age, is largely linked to the transcription cofactor vestigial-like 3 (vgll3). Here, we show that despite this simple genetic architecture, vgll3 genotype influences maturation age through a complex regulatory mechanism whereby it controls the expression of diverse pubertal signaling pathways. Using a multiomic approach in salmon testes, we show that the vgll3 genotype conferring early maturity up-regulates key genes controlling androgen production, cellular energy and adiposity, and TGF-β signaling, thereby increasing the likelihood of earlier pubertal initiation. By mapping VGLL3 regulatory elements we further show its interaction with distinct transcription factors in a genotype-dependent manner, thus coordinating differential activation of regulatory pathways. This study reveals the proximate mechanisms through which a genetically simple association leads to functionally complex molecular differences in a spectrum of cellular traits, thus explaining the molecular basis of pleiotropy in a large-effect gene. Our results indicate that evolution in correlated phenotypes, as exemplified by alternative life history strategies, can be dictated by the function of major life-history genes. [ABSTRACT FROM AUTHOR]

Familial adenomatous polyposis (FAP) is a colorectal cancer (CRC) predisposition syndrome characterized by the presence of numerous colorectal adenomatous polyps, resulting from a single germline, heterozygous, likely pathogenic/pathogenic (LP/P) variant in the APC gene, an important tumor suppressor encoding gene. Classic FAP is considered in individuals with a germline LP/P variant in APC and have ≥100 colorectal adenomatous polyps beginning on average in adolescence, while attenuated FAP typically presents with fewer colorectal adenomatous polyps (10-<100 polyps) in adulthood. Both forms can feature extracolonic manifestations, such as desmoid tumors, thyroid cancer, and osteomas. Reported genotype-phenotype correlations in FAP provide valuable insights for healthcare providers, but variable expressivity persists even among individuals sharing a genotype. In this case study, we report two patients with the same pathogenic APC variant [c.4348C>T, p.Arg1450Ter] and different presentations and clinical findings. Case 1 describes a 21-year-old male with an extensive family history of cancer who was diagnosed with FAP at age 4. Case 2 describes a 22-year-old female with no family history who was diagnosed with FAP after she initially presented with a desmoid tumor. Despite genetic similarities, their clinical courses significantly differed, emphasizing the variable expressivity of FAP. These cases highlight the importance of individual management and surveillance, as genotype alone may not predict clinical outcomes. They also underscore the need for further research into factors that influence FAP expressivity. [ABSTRACT FROM AUTHOR]

• A novel primary culturing technique for eccrine sweat glands (ESG) established. • ESG culture allows for functional ion transport measurement to inform therapy. • ESG culture allows for study of tissue-specific genotype-phenotype heterogeneity. • First scRNA-seq dataset of microdissected ESGs. Sweat chloride concentration is used both for CF diagnosis and for tracking CFTR modulator efficacy over time, but the relationship between sweat chloride and lung health is heterogeneous and informed by CFTR genotype. Here, we endeavored to characterize ion transport in eccrine sweat glands (ESGs). First, ESGs were microdissected from a non-CF skin donor to analyze individual glands. We established primary cultures of ESG cells via conditional reprogramming for functional testing of ion transport by short circuit current measurement and examined cell composition by single-cell RNA-sequencing (scRNA-seq) comparing with whole dissociated ESGs. Secondly, we cultured nasal epithelial (NE) cells and ESGs from two people with CF (pwCF) to assess modulator efficacy. Finally, NEs and ESGs were grown from one person with the CFTR genotype F312del/F508del to explore genotype-phenotype heterogeneity. ESG primary cells from individuals without CF demonstrated robust ENaC and CFTR function. scRNA-seq demonstrated both secretory and ductal ESG markers in cultured ESG cells. In both NEs and ESGs from pwCF homozygous for F508del, minimal baseline CFTR function was observed, and treatment with CFTR modulators significantly enhanced function. Notably, NEs from an individual bearing F312del/F508del exhibited significant baseline CFTR function, whereas ESGs from the same person displayed minimal CFTR function, consistent with observed phenotype. This study has established a novel primary culture technique for ESGs that allows for functional ion transport measurement to assess modulator efficacy and evaluate genotype-phenoytpe heterogeneity. To our knowledge, this is the first reported application of conditional reprogramming and scRNA-seq of microdissected ESGs. [ABSTRACT FROM AUTHOR]

Inherited retinal diseases (IRDs) are a clinically and genetically diverse group of progressive degenerative disorders that can result in severe visual impairment or complete blindness. Despite their predominantly monogenic inheritance patterns, the genetic complexity of over 300 identified disease-causing genes presents a significant challenge in correlating clinical phenotypes with genotypes. Achieving a molecular diagnosis is crucial for providing patients with definitive diagnostic clarity and facilitating access to emerging gene-based therapies and ongoing clinical trials. Recent advances in next-generation sequencing technologies have markedly enhanced our ability to identify genes and genetic defects leading to IRDs, thereby propelling the development of gene-based therapies. The clinical success of voretigene neparvovec (Luxturna), the first approved retinal gene therapy for RPE65-associated Leber congenital amaurosis (LCA), has spurred considerable research and development in gene-based therapies, highlighting the importance of reviewing the current status of gene therapy for IRDs, particularly those utilizing adeno-associated virus (AAV)-based therapies. As novel disease-causing mutations continue to be discovered and more targeted gene therapies are developed, integrating these treatment opportunities into the standard care for IRD patients becomes increasingly critical. This review provides an update on the diverse phenotypic–genotypic landscape of IRDs, with a specific focus on recent advances in the understanding of IRDs in children with infantile nystagmus syndrome (INS). We highlight the complexities of the genotypic–phenotypic landscape of INS-associated IRDs, including conditions such as achromatopsia, LCA, congenital stationary night blindness, and subtypes of retinitis pigmentosa. Additionally, we provide an updated overview of AAV-based gene therapies for these diseases and discuss the potential of gene-based therapies for underlying IRDs that lead to INS, offering a valuable resource for pediatric patients potentially eligible for ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex, brainstem, and spinal cord. While the typical clinical phenotype of ALS involves both upper and lower motor neurons, human and animal studies over the years have highlighted the potential spread to other motor and non-motor regions, expanding the phenotype of ALS. Although superoxide dismutase 1 (SOD1) mutations represent a minority of ALS cases, the SOD1 gene remains a milestone in ALS research as it represents the first genetic target for personalized therapies. Despite numerous single case reports or case series exhibiting extramotor symptoms in patients with ALS mutations in SOD1 (SOD1-ALS), no studies have comprehensively explored the full spectrum of extramotor neurological manifestations in this subpopulation. In this narrative review, we analyze and discuss the available literature on extrapyramidal and non-motor features during SOD1-ALS. The multifaceted expression of SOD1 could deepen our understanding of the pathogenic mechanisms, pointing towards a multidisciplinary approach for affected patients in light of new therapeutic strategies for SOD1-ALS.

Abstract Background Human patients with Ehlers‐Danlos syndrome (EDS) are categorized into subtypes based on causative genetic variants and phenotypes. The classical form of EDS, primarily caused by variants in COL5A1 or COL5A2, is a very common subtype in people but is poorly characterized in dogs. Objective Describe likely causal COL5A1 variants in dogs with classical EDS, summarize clinical histories, discuss potential disease mechanisms, and draw conclusions about disease prognosis. Animals Seven client‐owned dogs that exhibited clinical signs of classical EDS. Methods Clinical information was recorded from medical records and communication with attending veterinarians and dog owners. To identify potential causal gene sequence variants whole‐genome sequence analyses (n = 6) or Sanger sequencing (n = 1) were performed on DNA isolated from the probands. Pathological abnormalities in skin biopsy samples were assessed using histology and electron microscopy in 3 dogs. Results Six distinct heterozygous COL5A1 sequence variants were identified. The most common clinical signs included fragile skin (n = 7), hyperextensible skin (n = 7), joint hypermobility (n = 6), and atrophic scars (n = 5). The median age at last follow‐up or death was 12 years (range, 6.5‐14 years). Ultrastructural abnormalities in dermal collagen differed among dogs with different COL5A1 variants. Conclusion and Clinical Importance We describe the genotypic and phenotypic spectrum of the classical subtype of EDS by identifying 6 novel COL5A1 variants in conjunction with detailed clinical histories that included long‐term follow‐up information in 7 dogs.

Abstract Background Decoding human genomic sequences requires comprehensive analysis of DNA sequence functionality. Through computational and experimental approaches, researchers have studied the genotype-phenotype relationship and generate important datasets that help unravel complicated genetic blueprints. Thus, the recently developed artificial intelligence methods can be used to interpret the functions of those DNA sequences. Methods This study explores the use of deep learning, particularly pre-trained genomic models like DNA_bert_6 and human_gpt2-v1, in interpreting and representing human genome sequences. Initially, we meticulously constructed multiple datasets linking genotypes and phenotypes to fine-tune those models for precise DNA sequence classification. Additionally, we evaluate the influence of sequence length on classification results and analyze the impact of feature extraction in the hidden layers of our model using the HERV dataset. To enhance our understanding of phenotype-specific patterns recognized by the model, we perform enrichment, pathogenicity and conservation analyzes of specific motifs in the human endogenous retrovirus (HERV) sequence with high average local representation weight (ALRW) scores. Results We have constructed multiple genotype-phenotype datasets displaying commendable classification performance in comparison with random genomic sequences, particularly in the HERV dataset, which achieved binary and multi-classification accuracies and F1 values exceeding 0.935 and 0.888, respectively. Notably, the fine-tuning of the HERV dataset not only improved our ability to identify and distinguish diverse information types within DNA sequences but also successfully identified specific motifs associated with neurological disorders and cancers in regions with high ALRW scores. Subsequent analysis of these motifs shed light on the adaptive responses of species to environmental pressures and their co-evolution with pathogens. Conclusions These findings highlight the potential of pre-trained genomic models in learning DNA sequence representations, particularly when utilizing the HERV dataset, and provide valuable insights for future research endeavors. This study represents an innovative strategy that combines pre-trained genomic model representations with classical methods for analyzing the functionality of genome sequences, thereby promoting cross-fertilization between genomics and artificial intelligence.

Pompe disease (PD) is a rare autosomal recessive lysosomal disorder caused by loss‐of‐function of the α‐glucosidase (GAA) gene. The deficient GAA enzyme activity may result in potential life‐threatening muscle weakness, thus requiring a rapid diagnosis to initiate therapeutic interventions. In this large retrospective study, we analyzed 30.836 PD suspect samples from 57 countries using a two‐step approach utilizing dried blood spots (DBSs): biochemical testing of GAA activity followed by complementary genetic sequencing of GAA in biochemically conspicuous cases. Of these 30.836 samples, 2% (n = 639) were excluded; accordingly, this study consisted of 30.193 cases. Biochemical testing of GAA enzyme activity showed normal values in 28.354 (93.90%) and enzyme activity below the cut‐off in 1843 (6.10%) cases. These biochemically suspicious cases were genetically analyzed. We identified 723 Pompe cases with 283 different GAA alterations, and 98 variants have been unpublished so far. The most common variant was the splice variant c.‐32‐13T>G (IVS1). Looking at the IVS1‐genotype, the majority was compound heterozygous (n = 169) and identified in late‐onset cases (n = 162). Comparison of early‐ versus late‐onset cases to evaluate whether certain genotypes correlate with the age of onset revealed that homozygosity was predominantly found in infantile (85.65%) and compound heterozygosity in late‐onset (76.9%) cases. Analysis of homozygous cases revealed 61% nonsense variants in the early stages and 87% missense variants in the late stages. Mapping of disease‐associated (homozygous) missense variants to functional GAA protein domains showed that missense variants were found throughout GAA, but we identified enrichment in the catalytic domain. A strict genotype–phenotype correlation cannot be established; nevertheless, a phenotypic implication of some GAA variants could be drawn (e.g., c.896T>C/p.L299P, c.2015G>A/p.R672Q, and c.‐32‐13T>G). The combined enzyme activity and genetic testing from DBS cards can reliably identify PD and significantly accelerate diagnosis. We identified new genetic variants that contribute to the spectrum of pathogenic variants of the GAA gene. [ABSTRACT FROM AUTHOR]

Objective: Tooth agenesis is a common craniofacial malformation, which is often associated with gene mutations. The purpose of this research was to investigate and uncover ectodysplasin A (EDA) gene variants in eight Chinese families affected with tooth agenesis. Methods: Genomic DNA was extracted from tooth agenesis families and sequenced using whole‐exome sequencing. The expression of ectodysplasin A1 (EDA1) protein was studied by western blot, binding activity with receptor was tested by pull‐down and the NF‐κB transcriptional activity was analyzed by Dual luciferase assay. Results: Eight EDA missense variants were discovered, of which two (c.T812C, c.A1073G) were novel. The bioinformatics analysis indicated that these variants might be pathogenic. The tertiary structure analysis revealed that these eight variants could cause structural damage to EDA proteins. In vitro functional studies demonstrated that the variants greatly affect protein stability or impair the EDA‐EDAR interaction; thereby significantly affecting the downstream NF‐κb transcriptional activity. In addition, we summarized the genotype–phenotype correlation caused by EDA variants and found that EDA mutations leading to NSTA are mostly missense mutations located in the TNF domain. Conclusion: Our results broaden the variant spectrum of the EDA gene associated with tooth agenesis and provide valuable information for future genetic counseling. [ABSTRACT FROM AUTHOR]

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Clustered regularly interspaced short palindromic repeats (CRISPR) has revolutionized the field of genome editing. To circumvent the permanent modifications made by traditional CRISPR techniques and facilitate the study of both essential and nonessential genes, CRISPR interference (CRISPRi) was developed. This gene-silencing technique employs a deactivated Cas effector protein and a guide RNA to block transcription initiation or elongation. Continuous improvements and a better understanding of the mechanism of CRISPRi have expanded its scope, facilitating genome-wide high-throughput screens to investigate the genetic basis of phenotypes. Additionally, emerging CRISPR-based alternatives have further expanded the possibilities for genetic screening. This review delves into the mechanism of CRISPRi, compares it with other high-throughput gene-perturbation techniques, and highlights its superior capacities for studying complex microbial traits. We also explore the evolution of CRISPRi, emphasizing enhancements that have increased its capabilities, including multiplexing, inducibility, titratability, predictable knockdown efficacy, and adaptability to nonmodel microorganisms. Beyond CRISPRi, we discuss CRISPR activation, RNA-targeting CRISPR systems, and single-nucleotide resolution perturbation techniques for their potential in genome-wide high-throughput screens in microorganisms. Collectively, this review gives a comprehensive overview of the general workflow of a genome-wide CRISPRi screen, with an extensive discussion of strengths and weaknesses, future directions, and potential alternatives. [ABSTRACT FROM AUTHOR]

Background: Human patients with Ehlers‐Danlos syndrome (EDS) are categorized into subtypes based on causative genetic variants and phenotypes. The classical form of EDS, primarily caused by variants in COL5A1 or COL5A2, is a very common subtype in people but is poorly characterized in dogs. Objective: Describe likely causal COL5A1 variants in dogs with classical EDS, summarize clinical histories, discuss potential disease mechanisms, and draw conclusions about disease prognosis. Animals: Seven client‐owned dogs that exhibited clinical signs of classical EDS. Methods: Clinical information was recorded from medical records and communication with attending veterinarians and dog owners. To identify potential causal gene sequence variants whole‐genome sequence analyses (n = 6) or Sanger sequencing (n = 1) were performed on DNA isolated from the probands. Pathological abnormalities in skin biopsy samples were assessed using histology and electron microscopy in 3 dogs. Results: Six distinct heterozygous COL5A1 sequence variants were identified. The most common clinical signs included fragile skin (n = 7), hyperextensible skin (n = 7), joint hypermobility (n = 6), and atrophic scars (n = 5). The median age at last follow‐up or death was 12 years (range, 6.5‐14 years). Ultrastructural abnormalities in dermal collagen differed among dogs with different COL5A1 variants. Conclusion and Clinical Importance: We describe the genotypic and phenotypic spectrum of the classical subtype of EDS by identifying 6 novel COL5A1 variants in conjunction with detailed clinical histories that included long‐term follow‐up information in 7 dogs. [ABSTRACT FROM AUTHOR]

LAMA2‐related dystrophies (LAMA2‐RD) constitute a rare neuromuscular disorder with a broad spectrum of phenotypic severity. Our understanding of the genotype–phenotype correlations in this condition remains incomplete, and reliable clinical data for clinical trial readiness is limited. In this retrospective study, we reviewed the genetic data and medical records of 114 LAMA2‐RD patients enrolled at seven research centers in Brazil. We identified 58 different pathogenic variants, including 21 novel ones. Six variants were more prevalent and were present in 81.5% of the patients. Notably, the c.1255del, c.2049_2050del, c.3976 C>T, c.5234+1G>A, and c.4739dup variants were found in patients unable to walk and without cortical malformation. In contrast, the c.2461A>C variant was present in patients who could walk unassisted. Among ambulatory patients, missense variants were more prevalent (p < 0.0001). Although no specific hotspot regions existed in the LAMA2, 51% of point mutations were in the LN domain, and 88% of the missense variants were found within this domain. Functional analysis was performed in one intronic variant (c.4960‐17C>A) and revealed an out‐of‐frame transcript, indicating that the variant creates a cryptic splicing site (AG). Our study has shed light on crucial phenotype–genotype correlations and provided valuable insights, particularly regarding the Latin American population. [ABSTRACT FROM AUTHOR]

Glycogen storage diseases (GSDs) are abnormally inherited glycogen metabolism mainly affecting the liver, muscles, and heart. Deficiency of proteins involved in glycogen metabolism caused by genetic mutations are responsible for different subtype of GSDs. However, there are still some challenges in diagnosing GSD. This study includes 39 suspected GSDs patients from unrelated families in China. Next‐generation sequencing (NGS) was used to investigate the reason for their diseases at the genetic level. Finally, all 39 patients were diagnosed with GSDs, including 20 GSD‐Ia, 4 GSD‐VI, and 15 GSD IX (12 GSD‐IXa patients and 3 GSD‐IXb patients). Thirty‐two mutations in G6PC1, PYGL, PHKA2, and PHKB genes were identified, with 14 of them being novel variants. The pathogenicity of novel variants was classified according to ACMG guildlines and predicted by in slico algorithms. Mutations p.L216L and p.R83H in G6PC1 gene may be the hot spot mutation in Chinese. Hearing impairment is a rare clinical feature of GSD Ia, which has also been observed in our cohort. The severity of GSD VI and IX was indicated by our patients. Close follow‐up should be applied to GSD VI and IX patients. Our findings provided evidence for building the phenotype–genotype of GSDs and expanded the mutation spectrum of related genes. [ABSTRACT FROM AUTHOR]

Purpose: To describe the phenotype of Danish patients with genetically verified achromatopsia (ACHM) with special focus on signs of progression on structural or functional parameters, and possible genotype–phenotype correlations. Methods: Forty‐eight patients were identified, with disease‐causing variants in five different genes: CNGA3, CNGB3, GNAT2, PDE6C and PDE6H. Longitudinal evaluation was possible for 11 patients and 27 patients participated in a renewed in‐depth phenotyping consisting of visual acuity assessment, optical coherence tomography (OCT), fundus autofluorescence, colour vision evaluation, contrast sensitivity, mesopic microperimetry and full‐field electroretinography. Foveal morphology was evaluated based on OCT images for all 48 patients using a grading system based on the integrity of the hyperreflective photoreceptor band, the inner segment ellipsoid zone (ISe). Signs of progression were evaluated based on longitudinal data and correlation with age. Results: We found a statistically significant positive correlation between OCT grade and age (Spearman ρ = 0.62, p < 0.0001) and we observed changes in the foveal morphology in 2 of 11 patients with ≥5 years of follow‐up. We did not find any convincing correlation between age and functional parameters (visual acuity, retinal sensitivity and contrast sensitivity) nor did we find correlation between structural and functional parameters, or any clear genotype–phenotype correlation. Conclusions: Some patients with ACHM demonstrate signs of progressive foveal changes in OCT characteristics with increasing age. This is relevant in terms of possible new treatments. However, functional characteristics, such as visual acuity, remained stable despite changing foveal structure. Thus, seen from a patient perspective, ACHM can still be considered a non‐progressive condition. [ABSTRACT FROM AUTHOR]

Background: Decoding human genomic sequences requires comprehensive analysis of DNA sequence functionality. Through computational and experimental approaches, researchers have studied the genotype-phenotype relationship and generate important datasets that help unravel complicated genetic blueprints. Thus, the recently developed artificial intelligence methods can be used to interpret the functions of those DNA sequences. Methods: This study explores the use of deep learning, particularly pre-trained genomic models like DNA_bert_6 and human_gpt2-v1, in interpreting and representing human genome sequences. Initially, we meticulously constructed multiple datasets linking genotypes and phenotypes to fine-tune those models for precise DNA sequence classification. Additionally, we evaluate the influence of sequence length on classification results and analyze the impact of feature extraction in the hidden layers of our model using the HERV dataset. To enhance our understanding of phenotype-specific patterns recognized by the model, we perform enrichment, pathogenicity and conservation analyzes of specific motifs in the human endogenous retrovirus (HERV) sequence with high average local representation weight (ALRW) scores. Results: We have constructed multiple genotype-phenotype datasets displaying commendable classification performance in comparison with random genomic sequences, particularly in the HERV dataset, which achieved binary and multi-classification accuracies and F1 values exceeding 0.935 and 0.888, respectively. Notably, the fine-tuning of the HERV dataset not only improved our ability to identify and distinguish diverse information types within DNA sequences but also successfully identified specific motifs associated with neurological disorders and cancers in regions with high ALRW scores. Subsequent analysis of these motifs shed light on the adaptive responses of species to environmental pressures and their co-evolution with pathogens. Conclusions: These findings highlight the potential of pre-trained genomic models in learning DNA sequence representations, particularly when utilizing the HERV dataset, and provide valuable insights for future research endeavors. This study represents an innovative strategy that combines pre-trained genomic model representations with classical methods for analyzing the functionality of genome sequences, thereby promoting cross-fertilization between genomics and artificial intelligence. [ABSTRACT FROM AUTHOR]

Krabbe disease (KD) is an autosomal recessive neurodegenerative disorder caused by deficiency of the galactocerebrosidase (GALC) due to variants in the GALC gene. Here, we provide the first and the largest comprehensive analysis of clinical and genetic characteristics, and genotype–phenotype correlations of KD in Korean in comparison with other ethnic groups. From June 2010 to June 2023, 10 patients were diagnosed with KD through sequencing of GALC. Clinical features, and results of GALC sequencing, biochemical test, neuroimaging, and neurophysiologic test were obtained from medical records. An additional nine previously reported Korean KD patients were included for review. In Korean KD patients, the median age of onset was 2 years (3 months–34 years) and the most common phenotype was adult‐onset (33%, 6/18) KD, followed by infantile KD (28%, 5/18). The most frequent variants were c.683_694delinsCTC (23%) and c.1901T>C (23%), while the 30‐kb deletion was absent. Having two heterozygous pathogenic missense variants was associated with later‐onset phenotype. Clinical features were similar to those of other ethnic groups. In Korean KD patients, the most common phenotype was the adult‐onset type and the GALC variant spectrum was different from that of the Caucasian population. This study would further our understanding of KD. [ABSTRACT FROM AUTHOR]

Background: Using the Clinical Audit Research and Evaluation of Motor Neuron Disease (CARE-MND) database and the Scottish Regenerative Neurology Tissue Bank, we aimed to outline the genetic epidemiology and phenotypes of an incident cohort of people with MND (pwMND) to gain a realistic impression of the genetic landscape and genotype–phenotype associations. Methods: Phenotypic markers were identified from the CARE-MND platform. Sequence analysis of 48 genes was undertaken. Variants were classified using a structured evidence-based approach. Samples were also tested for C9orf72 hexanucleotide expansions using repeat-prime PCR methodology. Results: 339 pwMND donated a DNA sample: 44 (13.0%) fulfilled criteria for having a pathogenic variant/repeat expansion, 53.5% of those with a family history of MND and 9.3% of those without. The majority (30 (8.8%)) had a pathogenic C9orf72 repeat expansion, including two with intermediate expansions. Having a C9orf72 expansion was associated with a significantly lower Edinburgh Cognitive and Behavioural ALS Screen ALS-Specific score (p = 0.0005). The known pathogenic SOD1 variant p.(Ile114Thr), frequently observed in the Scottish population, was detected in 9 (2.7%) of total cases but in 17.9% of familial cases. Rare variants were detected in FUS and NEK1. One individual carried both a C9orf72 expansion and SOD1 variant. Conclusions: Our results provide an accurate summary of MND demographics and genetic epidemiology. We recommend early genetic testing of people with cognitive impairment to ensure that C9orf72 carriers are given the best opportunity for informed treatment planning. Scotland is enriched for the SOD1 p.(Ile114Thr) variant and this has significant implications with regards to future genetically-targeted treatments. [ABSTRACT FROM AUTHOR]

Moyamoya disease, a cerebrovascular disease leading to strokes in children and young adults, is characterized by progressive occlusion of the distal internal carotid arteries and the formation of collateral vessels. Altered genes play a prominent role in the etiology of moyamoya disease, but a causative gene is not identified in the majority of cases. Exome sequencing data from 151 individuals from 84 unsolved families were analyzed to identify further genes for moyamoya disease, then candidate genes assessed in additional cases (150 probands). Two families had the same rare variant in ANO1, which encodes a calcium-activated chloride channel, anoctamin-1. Haplotype analyses found the families were related, and ANO1 p.Met658Val segregated with moyamoya disease in the family with an LOD score of 3.3. Six additional ANO1 rare variants were identified in moyamoya disease families. The ANO1 rare variants were assessed using patch-clamp recordings, and the majority of variants, including ANO1 p.Met658Val, displayed increased sensitivity to intracellular Ca2+. Patients harboring these gain-of-function ANO1 variants had classic features of MMD, but also had aneurysm, stenosis, and/or occlusion in the posterior circulation. Our studies support that ANO1 gain-of-function pathogenic variants predispose to moyamoya disease and are associated with unique involvement of the posterior circulation.

The past decade has seen an explosion in the identification of genetic causes of neurodevelopmental disorders, including Mendelian, de novo, and somatic factors. These discoveries provide opportunities to understand cellular and molecular mechanisms as well as potential gene-gene and gene-environment interactions to support novel therapies. Stem cell-based models, particularly human brain organoids, can capture disease-associated alleles in the context of the human genome, engineered to mirror disease-relevant aspects of cellular complexity and developmental timing. These models have brought key insights into neurodevelopmental disorders as diverse as microcephaly, autism, and focal epilepsy. However, intrinsic organoid-to-organoid variability, low levels of certain brain-resident cell types, and long culture times required to reach maturity can impede progress. Several recent advances incorporate specific morphogen gradients, mixtures of diverse brain cell types, and organoid engraftment into animal models. Together with nonhuman primate organoid comparisons, mechanisms of human neurodevelopmental disorders are emerging.

Shovel-shaped incisors (SSI) and Carabelli's cusp (CC) are noteworthy human dental non-metric traits which presence and degree of expression have been reported to cluster within distinct populations. Recent advances in developmental biology suggest that SSI and CC are likely under polygenic developmental control; therefore, genetic variation in multiple genes is likely to contribute to differential SSI and CC expression. The exact genetic mechanisms underlying variation in SSI and CC development, however, remain mostly unknown. This study aims to identify whether variation in the basal DNA sequences of six candidate genes, NKX2-3, SOSTDC1, BMP4, FGF3, FGF4, and WNT10A, has any impact on SSI and/or CC expression. Study methods involve collection of saliva samples and dental data from 36 participants. The Arizona State University Dental Anthropology System (ASUDAS) has been used to score SSI and CC expression. Next-generation sequencing (NGS) methods were utilized to sequence the entire gene region of the candidate genes. Spearman's correlation test was used to score the relationship between the genotype and degree of trait expression of participants. Fifteen SNPs/INDELs belonging to SOSTDC1, FGF3, FGF4 and WNT10A were significantly associated with SSI and/or CC expression. No SNPs/INDELs were detected in the genes BMP4 and NKX2-3 that significantly contributes to observed phenotypes. FGF3, FGF4, SOSTDC1 and WNT10A were possibly involved in the formation of shoveling and Carabelli's cusp. However, because of the small sample size, more studies are needed to confirm their role and rule out any potential role of NKX2-3 and BMP4 in the production of SSI and CC. [ABSTRACT FROM AUTHOR]

Purpose: Dural ectasia (DE) may significantly impact Marfan syndrome (MFS) patients' quality of life due to chronic lower back pain, postural headache and urinary disorders. We aimed to evaluate the association of quantitative measurements of DE, and their evolution over time, with demographic, clinical and genetic characteristics in a cohort of MFS patients. Methods: We retrospectively included 88 consecutive patients (39% females, mean age 37.1 ± 14.2 years) with genetically confirmed MFS who underwent at least one MRI or CT examination of the lumbosacral spine. Vertebral scalloping (VS) and dural sac ratio (DSR) were calculated from L3 to S3. Likely pathogenic or pathogenic FBN1 variants were categorized as either protein-truncating or in-frame. The latter were further classified according to their impact on the cysteine content of fibrillin-1. Results: Higher values of the systemic score (revised Ghent criteria) were associated with greater DSR at lumbar (p < 0.001) and sacral (p = 0.021) levels. Patients with protein-truncating variants exhibited a greater annual increase in lumbar (p = 0.039) and sacral (p = 0.048) DSR. Mutations affecting fibrillin-1 cysteine content were linked to higher VS (p = 0.009) and DSR (p = 0.038) at S1, along with a faster increase in VS (p = 0.032) and DSR (p = 0.001) in the lumbar region. Conclusion: Our study shed further light on the relationship between genotype, dural pathology, and the overall clinical spectrum of MFS. The identification of protein-truncating variants and those impacting cysteine content may therefore suggest closer patient monitoring, in order to address potential complications associated with DE. [ABSTRACT FROM AUTHOR]

Background and Aims: This study aimed to report nine Charcot–Marie–Tooth disease (CMT) families with six novel IGHMBP2 mutations in our CMT2 cohort and to summarize the genetic and clinical features of all AR‐CMT2S patients reported worldwide. Methods: General information, clinical and neurophysiological data of 275 axonal CMT families were collected. Genetic screening was performed by inherited peripheral neuropathy related genes panel or whole exome sequencing. The published papers reporting AR‐CMT2S from 2014 to 2023 were searched in Pubmed and Wanfang databases. Results: In our CMT2 cohort, we detected 17 AR‐CMT2S families carrying IGHMBP2 mutations and eight were published previously. Among these, c.743 T > A (p.Val248Glu), c.884A > G (p.Asp295Gly), c.1256C > A (p.Ser419*), c.2598_2599delGA (p.Lys868Sfs*16), c.1694_1696delATG (p.Asp565del) and c.2509A > T (p.Arg837*) were firstly reported. These patients prominently presented with early‐onset typical axonal neuropathy and without respiratory dysfunction. So far, 56 AR‐CMT2S patients and 57 different mutations coming from 43 families have been reported in the world. Twenty‐nine of 32 missense mutations were clustered in helicase domain and ATPase region. The age at onset ranged from 0.11to 20 years (Mean ± SD: 3.43 ± 3.88 years) and the majority was infantile‐onset (<2 years). The initial symptoms included weakness of limbs (19, 29.7%), delayed milestones (12, 18.8%), gait disturbance (11, 17.2%), feet deformity (8, 12.5%), feet drop (8, 12.5%), etc. Interpretation: AR‐CMT2S accounted for 6.2% in our CMT2 cohort. We firstly reported six novel IGHMBP2 mutations which expanded the genotypic spectrum of AR‐CMT2S. Furthermore, 17 AR‐CMT2S families could provide more resources for natural history study, drug research and development. [ABSTRACT FROM AUTHOR]

Rubinstein–Taybi syndrome (RTS) is a rare genetic disorder characterized by intellectual disability, facial dysmorphisms, and enlarged thumbs and halluces. Approximately 55% of RTS cases result from pathogenic variants in the CREBBP gene, with an additional 8% linked to the EP300 gene. Given the close relationship between these two genes and their involvement in epigenomic modulation, RTS is grouped into chromatinopathies. The extensive clinical heterogeneity observed in RTS, coupled with the growing number of disorders involving the epigenetic machinery, poses a challenge to a phenotype-based diagnostic approach for these conditions. Here, we describe the first case of a patient clinically diagnosed with RTS with a CREBBP truncating variant in mosaic form. We also review previously described cases of mosaicism in CREBBP and apply clinical diagnostic guidelines to these patients, confirming the good specificity of the consensus. Nonetheless, these reports raise questions about the potential underdiagnosis of milder cases of RTS. The application of a targeted phenotype-based approach, coupled with high-depth NGS, may enhance the diagnostic yield of whole-exome sequencing (WES) in mild and mosaic conditions. [ABSTRACT FROM AUTHOR]

Delineation of a developmental and behavioral trajectory is a key‐topic in the context of a genetic syndrome. Short‐ and long‐term implications concerning school outcome, independent living, and working opportunities are strictly linked to the cognitive and behavioral profile of an individual. For the first time, we present a longitudinal characterization of the adaptive and behavioral profile of a pediatric sample of 32 individuals with Sotos Syndrome (SoS) (18 males, 14 females; mean age 9.7 ± 4 years, eight carrying the NSD1 5q35 microdeletion and 24 with an intragenic mutation). We performed two clinical assessments: at baseline (T0) and at distance evaluation (T1) of adaptive and behavioral skills with a mean distance of 1.56 ± 0.95 years among timepoints. Our study reports a stability over the years—meant as lack of statistically significant clinical worsening or improvement—of both adaptive and behavioral skills investigated, regardless the level of Intellectual Quotient and chronological age at baseline. However, participants who did not discontinue intervention among T0 and T1, were characterized by a better clinical profile in terms of adaptive skills and behavioral profile at distance, emphasizing that uninterrupted intervention positively contributes to the developmental trajectory. [ABSTRACT FROM AUTHOR]

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. AMPARs form by homo- or heteromeric assembly of subunits encoded by the GRIA1 – GRIA4 genes, of which only GRIA3 is X-chromosomal. Increasing numbers of GRIA3 missense variants are reported in patients with neurodevelopmental disorders (NDD), but only a few have been examined functionally. Here, we evaluated the impact on AMPAR function of one frameshift and 43 rare missense GRIA3 variants identified in patients with NDD by electrophysiological assays. Thirty-one variants alter receptor function and show loss-of-function or gain-of-function properties, whereas 13 appeared neutral. We collected detailed clinical data from 25 patients (from 23 families) harbouring 17 of these variants. All patients had global developmental impairment, mostly moderate (9/25) or severe (12/25). Twelve patients had seizures, including focal motor (6/12), unknown onset motor (4/12), focal impaired awareness (1/12), (atypical) absence (2/12), myoclonic (5/12) and generalized tonic-clonic (1/12) or atonic (1/12) seizures. The epilepsy syndrome was classified as developmental and epileptic encephalopathy in eight patients, developmental encephalopathy without seizures in 13 patients, and intellectual disability with epilepsy in four patients. Limb muscular hypotonia was reported in 13/25, and hypertonia in 10/25. Movement disorders were reported in 14/25, with hyperekplexia or non-epileptic erratic myoclonus being the most prevalent feature (8/25). Correlating receptor functional phenotype with clinical features revealed clinical features for GRIA3 -associated NDDs and distinct NDD phenotypes for loss-of-function and gain-of-function variants. Gain-of-function variants were associated with more severe outcomes: patients were younger at the time of seizure onset (median age: 1 month), hypertonic and more often had movement disorders, including hyperekplexia. Patients with loss-of-function variants were older at the time of seizure onset (median age: 16 months), hypotonic and had sleeping disturbances. Loss-of-function and gain-of-function variants were disease-causing in both sexes but affected males often carried de novo or hemizygous loss-of-function variants inherited from healthy mothers, whereas affected females had mostly de novo heterozygous gain-of-function variants. [ABSTRACT FROM AUTHOR]

A growing body of work has addressed human adaptations to diverse environments using genomic data, but few studies have connected putatively selected alleles to phenotypes, much less among underrepresented populations such as Amerindians. Studies of natural selection and genotype-phenotype relationships in underrepresented populations hold potential to uncover previously undescribed loci underlying evolutionarily and biomedically relevant traits. Here, we worked with the Tsimane and the Moseten, two Amerindian populations inhabiting the Bolivian lowlands. We focused most intensively on the Tsimane, because long-term anthropological work with this group has shown that they have a high burden of both macro and microparasites, as well as minimal cardiometabolic disease or dementia. We therefore generated genome-wide genotype data for Tsimane individuals to study natural selection, and paired this with blood mRNA-seq as well as cardiometabolic and immune biomarker data generated from a larger sample that included both populations. In the Tsimane, we identified 21 regions that are candidates for selective sweeps, as well as 5 immune traits that show evidence for polygenic selection (e.g., C-reactive protein levels and the response to coronaviruses). Genes overlapping candidate regions were strongly enriched for known involvement in immune-related traits, such as abundance of lymphocytes and eosinophils. Importantly, we were also able to draw on extensive phenotype information for the Tsimane and Moseten and link five regions (containing PSD4, MUC21 and MUC22, TOX2, ANXA6, and ABCA1) with biomarkers of immune and metabolic function. Together, our work highlights the utility of pairing evolutionary analyses with anthropological and biomedical data to gain insight into the genetic basis of health-related traits.

Abstract Purpose The goal of the study was to search for novel bi-allelic CRB1 mutations, and then to analyze the CRB1 literature at the genotypic and phenotypic levels. Approach We screened various variables such as the CRB1 mutation types, domains, exons, and genotypes and their relation with specific ocular phenotypes. An emphasis was given to the bi-allelic missense and nonsense mutations because of their high prevalence compared to other mutation types. Finally, we quantified the effect of various non-modifiable factors over the best-corrected visual acuity oculus uterque (BCVA OU) using multivariate linear regression models and identified genetic interactions. Results A novel bi-allelic missense in the exon 9 of CRB1; c.2936G > A; p.(Gly979Asp) was found to be associated with rod-cone dystrophy (RCD). CRB1 mutation type, exons, domains, and genotype distribution varied significantly according to fundus characteristics, such as peripheral pigmentation and condition, optic disc, vessels, macular condition, and pigmentation (P

Retinitis pigmentosa (RP) associated with biallelic variants in CDHR1 has rarely been reported, and detailed phenotyping data are not available. RP implies relative preservation of foveal cones, when compared to cone-rod dystrophy associated with biallelic null variants in CDHR1. We hypothesize that RP may occur in association with one or more hypomorphic CDHR1 alleles. Retrospective report of a 48-year-old patient with CDHR1-associated RP with a hypomorphic missense variant c.562 G>A, p. (Gly188Ser) and a novel, unreported variant affecting a canonical splice acceptor site (c.784–1 G>C). Clinical examination, multimodal retinal imaging, electroretinography, visual field testing, and mesopic microperimetry were undertaken 8 years apart. Scotopic microperimetry was also performed. The DNA sequence context of the variants was examined to identify theoretical CRISPR-Cas9 base-editing strategies. The patient presented at 35 years with a 12-year history of nyctalopia. His best corrected visual acuity was 20/20. Clinical presentation, multimodal retinal imaging studies, electroretinography, and mesopic microperimetry were typical of a progressive rod-cone dystrophy (i.e. classic RP). There were no scotomas within the central field as would be expected at this age in CDHR1-associated cone-rod dystrophy. Scotopic microperimetry suggested some preservation of macular cone over rod function, although both were severely impaired. A suitable CRISPR adenine base editor was identified that could theoretically correct the missense variant c.562 G>A, p. (Gly188Ser). CDHR1-associated RP shows a relative preservation of cone function in the presence of a presumed hypomorphic allele and may be considered a hypomorphic disease phenotype. Further work is required to identify modifying factors that determine disease phenotype since macular dystrophy, with relative sparing of rods, may also occur with hypomorphic CDHR1 alleles [ABSTRACT FROM AUTHOR]

(1) Background: Cockayne syndrome (CS) is an ultra-rare multisystem disorder, classically subdivided into three forms and characterized by a clinical spectrum without a clear genotype-phenotype correlation for both the two causative genes ERCC6 (CS type B) and ERCC8 (CS type A). We assessed this, presenting a series of patients with genetically confirmed CSB. (2) Materials and Methods: We retrospectively collected demographic, clinical, genetic, neuroimaging, and serum neurofilament light-chain (sNFL) data about CSB patients; diagnostic and severity scores were also determined. (3) Results: Data of eight ERCC6/CSB patients are presented. Four patients had CS I, three patients CS II, and one patient CS III. Various degrees of ataxia and spasticity were cardinal neurologic features, with variably combined systemic characteristics. Mean age at diagnosis was lower in the type II form, in which classic CS signs were more evident. Interestingly, sNFL determination appeared to reflect clinical classification. Two novel premature stop codon and one novel missense variants were identified. All CS I subjects harbored the p.Arg735Ter variant; the milder CS III subject carried the p.Leu764Ser missense change. (4) Conclusion: Our work confirms clinical variability also in the ERCC6/CSB type, where manifestations may range from severe involvement with prenatal or neonatal onset to normal psychomotor development followed by progressive ataxia. We propose, for the first time in CS, sNFL as a useful peripheral biomarker, with increased levels compared to currently available reference values and with the potential ability to reflect disease severity. [ABSTRACT FROM AUTHOR]

Iron resistance iron deficiency anaemia is a rare autosomal recessive disorder characterized by hypochromic microcytic anaemia, low transferrin saturation and inappropriately high hepcidin levels. The aetiology of this condition is rooted in genetic variations within the transmembrane serine protease 6 (TMPRSS6) genes, responsible for encoding matriptase-2, a pivotal negative regulator of hepcidin. We conducted a systematic search across four electronic databases, yielding 538 articles in total out of which 25 were finally included and were preceded further, aiming to prognosticate prevalent single nucleotide polymorphisms (SNPs) and detrimental genetic alterations. This review aims to elucidate the effects of various SNPs and pathogenic mutations on both haematological and biochemical parameters, as well as their potential interethnic correlation. Employing bioinformatics tools, we subjected over 100 SNPs to scrutiny, discerning their potential functional ramifications. We found rs1373272804, rs1430692214 and rs855791 variants to be most frequent and were having a significant impact on haematological and biochemical profile. We found that individuals of European ancestry were more prone to have these variants compared to other ethnic groups. In conclusion, this review not only sheds light on the association of TMPRSS6 polymorphism in iron resistance iron deficiency anaemia (IRIDA), but also highlights the critical need for further investigations involving larger sample size and more diverse ethnic groups around the globe. These future studies will be vital for gaining a stronger and more reliable understanding of how these genetic differences are linked to the development of IRIDA. [ABSTRACT FROM AUTHOR]

To date, no publicly accessible platform has captured and synthesized all of the layered dimensions of genotypic, phenotypic, and mechanistic information published in the field of inborn errors of immunity (IEIs). Such a platform would represent the extensive and complex landscape of IEIs and could increase the rate of diagnosis in patients with a suspected IEI, which remains unacceptably low. Our aim was to create an expertly curated, patient-centered, multidimensional IEI database that enables aggregation and sophisticated data interrogation and promotes involvement from diverse stakeholders across the community. The database structure was designed following a subject-centered model and written in Structured Query Language (SQL). The web application is written in Hypertext Preprocessor (PHP), Hypertext Markup Language (HTML), Cascading Style Sheets (CSS), and JavaScript. All data stored in the Genetic Immunology Advisor (GenIA) are extracted by manually reviewing published research articles. We completed data collection and curation for 24 pilot genes. Using these data, we have exemplified how GenIA can provide quick access to structured, longitudinal, more thorough, comprehensive, and up-to-date IEI knowledge than do currently existing databases, such as ClinGen, Human Phenotype Ontology (HPO), ClinVar, or Online Mendelian Inheritance in Man (OMIM), with which GenIA intends to dovetail. GenIA strives to accurately capture the extensive genetic, mechanistic, and phenotypic heterogeneity found across IEIs, as well as genetic paradigms and diagnostic pitfalls associated with individual genes and conditions. The IEI community's involvement will help promote GenIA as an enduring resource that supports and improves knowledge sharing, research, diagnosis, and care for patients with genetic immune disease. [ABSTRACT FROM AUTHOR]

Seasonal shedding of winter hair at the start of summer is well studied in wild and domesticated populations. However, the genetic influences on this trait and their interactions are poorly understood. We use data from 13,364 cattle with 36,899 repeated phenotypes to investigate the relationship between hair shedding and environmental variables, single nucleotide polymorphisms, and their interactions to understand quantitative differences in seasonal shedding. Using deregressed estimated breeding values from a repeated records model in a genome-wide association analysis (GWAA) and meta-analysis of year-specific GWAA gave remarkably similar results. These GWAA identified hundreds of variants associated with seasonal hair shedding. There were especially strong associations between chromosomes 5 and 23. Genotype-by-environment interaction GWAA identified 1,040 day length-by-genotype interaction associations and 17 apparent temperature-by-genotype interaction associations with hair shedding, highlighting the importance of day length on hair shedding. Accurate genomic predictions of hair shedding were created for the entire dataset, Angus, Hereford, Brangus, and multibreed datasets. Loci related to metabolism and light-sensing have a large influence on seasonal hair shedding. This is one of the largest genetic analyses of a phenological trait and provides insight into both agriculture production and basic science. [ABSTRACT FROM AUTHOR]

Introduction: Genetic forms of growth hormone deficiency (GHD) may occur as isolated GHD (IGHD) or as a component of multiple pituitary hormone deficiency (MPHD). This study aimed to present the clinical and molecular characteristics of patients with IGHD/MPHD due to the GH1 gene variants. Methods: A gene panel accommodating 25 genes associated with MPHD and short stature was used to search for small sequence variants. Multiplex ligation-dependent probe amplification was performed in patients with normal panel results to investigate gross deletion/duplications. Segregation in the family was performed by Sanger sequencing. Results: The GH1 gene variants were detected in 5 patients from four unrelated families. One patient had IGHD IA due to homozygous whole GH1 gene deletion and one had IGHD IB due to novel homozygous c.162C>G/p.(Tyr54*) variant. Two patients from a family had previously reported heterozygous c.291+1G>A/p.(?) variant in which clinical and genetic characteristics were compatible with IGHD II accompanying MPHD. One patient had clinical and laboratory characteristics of IGHD II with MPHD but the heterozygous c.468 C>T/p.(R160W) variant had conflicting results about the relationship with the phenotype. Conclusion: Expanding our knowledge of the spectrum of GH1 gene variants by apprehending clinical and molecular data of more cases, helps to identify the genotype-phenotype correlation of IGHD/MPHD and the GH1 gene variants. These patients must be regularly followed up for the occurrence of additional pituitary hormone deficiencies. [ABSTRACT FROM AUTHOR]

Inherited retinal diseases (IRDs) are a clinically and genetically diverse group of progressive degenerative disorders that can result in severe visual impairment or complete blindness. Despite their predominantly monogenic inheritance patterns, the genetic complexity of over 300 identified disease-causing genes presents a significant challenge in correlating clinical phenotypes with genotypes. Achieving a molecular diagnosis is crucial for providing patients with definitive diagnostic clarity and facilitating access to emerging gene-based therapies and ongoing clinical trials. Recent advances in next-generation sequencing technologies have markedly enhanced our ability to identify genes and genetic defects leading to IRDs, thereby propelling the development of gene-based therapies. The clinical success of voretigene neparvovec (Luxturna), the first approved retinal gene therapy for RPE65-associated Leber congenital amaurosis (LCA), has spurred considerable research and development in gene-based therapies, highlighting the importance of reviewing the current status of gene therapy for IRDs, particularly those utilizing adeno-associated virus (AAV)-based therapies. As novel disease-causing mutations continue to be discovered and more targeted gene therapies are developed, integrating these treatment opportunities into the standard care for IRD patients becomes increasingly critical. This review provides an update on the diverse phenotypic–genotypic landscape of IRDs, with a specific focus on recent advances in the understanding of IRDs in children with infantile nystagmus syndrome (INS). We highlight the complexities of the genotypic–phenotypic landscape of INS-associated IRDs, including conditions such as achromatopsia, LCA, congenital stationary night blindness, and subtypes of retinitis pigmentosa. Additionally, we provide an updated overview of AAV-based gene therapies for these diseases and discuss the potential of gene-based therapies for underlying IRDs that lead to INS, offering a valuable resource for pediatric patients potentially eligible for ongoing clinical trials.

Background: MSX1 (OMIM #142983) is crucial to normal dental development, and variants in MSX1 are associated with dental anomalies. The objective of this study was to characterize the pathogenicity of novel MSX1 variants in Chinese families with non‐syndromic oligodontia (NSO). Methods: Genomic DNA was extracted from individuals representing 35 families with non‐syndromic oligodontia and was analyzed by Sanger sequencing and whole‐exome sequencing. Pathogenic variants were screened via analyses involving PolyPhen‐2, Sorting‐Intolerant from Tolerant, and MutationTaster, and conservative analysis of variants. Patterns of MSX1‐related NSO were analyzed. MSX1 structural changes suggested functional consequences in vitro. Results: Three previously unreported MSX1 heterozygous variants were identified: one insertion variant (c.576_577insTAG; p.Gln193*) and two missense variants (c. 871T>C; p.Tyr291His and c. 644A>C; p.Gln215Pro). Immunofluorescence analysis revealed abnormal subcellular localization of the p.Gln193* MSX1 variant. In addition, we found that these MSX1 variants likely lead to the loss of second premolars. Conclusion: Three novel MSX1 variants were identified in Chinese Han families with NSO, expanding the MSX1 variant spectrum and presenting a genetic origin for the pathogenesis detected in patients and their families. [ABSTRACT FROM AUTHOR]

A Chinese family was identified to have two patients with rickets, an adult female and a male child (proband), both exhibiting signs related to X-linked hypophosphatemic rickets (XLH). Gene sequencing analysis revealed a deletion of adenine at position 1985 (c.1985delA) in the PHEX-encoding gene. To investigate the relationship between this mutation and the pathogenicity of XLH, as well as analyze the effects of different dosages of PHEX gene mutations on clinical phenotypes, we developed a rat model carrying the PHEX deletion mutation. The CRISPR/Cas9 gene editing technology was employed to construct the rat model with the PHEX gene mutation (c.1985delA). Through reproductive procedures, five genotypes of rats were obtained: female wild type (X/X), female heterozygous (-/X), female homozygous wild type (-/-), male wild type (X/Y), and male hemizygous (-/Y). The rats with different genotypes underwent analysis of growth, serum biochemical parameters, and bone microstructure. The results demonstrated the successful generation of a stable ratmodel inheriting the PHEX gene mutation. Compared to thewild-type rats, the mutant rats displayed delayed growth, shorter femurs, and significantly reduced bone mass. Among the female rats, the homozygous individuals exhibited the smallest body size, decreased bone mass, shortest femur length, and severe deformities. Moreover, the mutant rats showed significantly lower blood phosphorus concentration, elevated levels of FGF23 and alkaline phosphatase, and increased expression of phosphorus regulators. In conclusion, the XLH rat model with the PHEX gene mutation dosage demonstrated its impact on growth and development, serum biochemical parameters, and femoral morphology. [ABSTRACT FROM AUTHOR]

Background: Uncovering distinct features and trajectories of amyotrophic lateral sclerosis (ALS) associated with SOD1 mutations (SOD1-ALS) can provide valuable insights for patient' counseling and stratification for trials, and interventions timing. Our study aims to pinpoint distinct clinical characteristics of SOD1-ALS by delving into genotype–phenotype correlations and factors that potentially impact disease progression. Methods: This is a retrospective observational study of a SOD1-ALS cohort from two Italian registers situated in the regions of Emilia-Romagna, Piedmont and Valle d'Aosta. Results: Out of 2204 genotyped ALS patients, 2.5% carried SOD1 mutations, with a M:F ratio of 0.83. SOD1-ALS patients were younger, and more frequently reported a family history of ALS and/or FTD. SOD1-ALS had a longer survival compared to patients without ALS-associated gene mutations. However, here was considerable variability in survival across distinct SOD1 mutations, with an average survival of less than a year for the L39V, G42S, G73S, D91N mutations. Among SOD1-ALS, multivariate analysis showed that, alongside established clinical prognostic factors such as advanced age at onset and high progression rate at diagnosis, mutations located in exon 2 or within highly conserved gene positions predicted worse survival. Conversely, among comorbidities, cancer history was independently associated with longer survival. Interpretation: Within the context of an overall slower disease, SOD1-ALS exhibits some degree of heterogeneity linked to the considerable genetic diversity arising from the multitude of potential mutations sites and specific clinical prognostic factors, including cancer history. Revealing the factors that modulate the phenotypic heterogeneity of SOD1-ALS could prove advantageous in improving the efficacy of upcoming therapeutic approaches. [ABSTRACT FROM AUTHOR]

Classic galactosemia (OMIM#230400) is an autosomal recessive inborn error of carbohydrate metabolism caused by a deficiency of the galactose‐1‐phosphate‐uridyl‐transferase enzyme encoded by the GALT gene. Even though a galactose‐restricted diet efficiently resolves the acute complications, it is insufficient to prevent long‐term complications regarding speech defects, intellectual functioning, premature ovarian failure, cataract, hepatomegaly, dysarthria, ataxia, and tremor. Seventy‐seven patients who were genetically diagnosed with classic galactosemia were included in this cohort. Identified novel variants were classified based on their predicted effect on the GALT function. Further, potential genotype–phenotype correlations were investigated via statistical analysis. In total, 18 different sequence variants were identified, including four novels (c.200delG/p.(Arg67Profs*19), c.533T>G/ p.(Met178Arg), c.708_709delGT/p.(Ser236Argfs*30), c.467C>A/p.(Ser156*)). Jaundice was the most common short‐term finding with 80% (61/77). Even with early diagnosis, intellectual disability is encountered with 36% (27/74) of the long‐term complications. Patients with biallelic missense variants have a significantly higher prevalence of cataracts (OR: 17.9). Longitudinal observations showed attenuation of cataracts and hepatomegaly. This study has shown the GALT variation spectrum of the Turkish population with a 30‐year retrospective cohort, submitting a significant contribution to the genotype/phenotype correlation in galactosemia. This study also highlights the cost‐effective importance of Sanger sequencing in the diagnosis of single‐gene metabolic diseases. [ABSTRACT FROM AUTHOR]

Prader-Willi syndrome (PWS) is a complex genetic disorder with three molecular classes but clinical ascertainment is based on distinctive features. The prevalence of dysmorphic features was studied in 355 PWS participants (61% deletion, 36% maternal disomy [UPD], and 3% imprinting defects) from the National Institute of Health PWS Rare Diseases Clinical Research Network. The effect of growth hormone (GH) treatment on growth and dysmorphic features was compared. Among participants, upslanting palpebral fissures were seen in 23%; strabismus in 42%; abnormal dentition in 32%; small hands in 63% and small feet in 70%; hypopigmentation in 30%; striae in 32% and skin picking in 26%. Compared to those with UPD, participants with deletions were found to be heavier (p = 0.002), had smaller head circumference (HC) (p = 0.009), higher incidence of a flat occiput (p = 0.005); low-anterior hairline (p = 0.04); abnormal dentition (p = 0.009); abdominal striae (p = 0.045), nail abnormalities (p = 0.050), and fair-haired (p

Introduction: Given the unique natural history of GBA-related Parkinson’s disease (GBA-PD) and the potential for novel treatments in this population, genetic testing prioritization for the identification of GBA-PD patients is crucial for prognostication, individualizing treatment, and stratification for clinical trials. Assessing the predictive value of certain clinical traits for the GBA-variant carrier status will help target genetic testing in clinical settings where cost and access limit its availability. Methods: In-depth clinical characterization through standardized rating scales for motor and non-motor symptoms and self-reported binomial information of a cohort of subjects with PD (n = 100) from our center and from the larger cohort of the Parkinson’s Progression Marker Initiative (PPMI) was utilized to evaluate the predictive values of clinical traits for GBA variant carrier status. The model was cross-validated across the two cohorts. Results: Leveraging non-motor symptoms of PD, we established successful discrimination of GBA variants in the PPMI cohort and study cohort (AUC 0.897 and 0.738, respectively). The PPMI cohort model successfully generalized to the study cohort data using both MDS-UPDRS scores and binomial data (AUC 0.740 and 0.734, respectively) while the study cohort model did not. Conclusions: We assessed the predictive value of non-motor symptoms of PD for identifying GBA carrier status in the general PD population. These data can be used to determine a simple, clinically oriented model using either the MDS-UPDRS or subjective symptom reporting from patients. Our results can inform patient counseling about the expected carrier risk and test prioritization for the expected identification of GBA variants.

• The p.Thr241Asn missense mutation in congenital Factor VII deficiency was frequent. • This mutation may be candidate as a good tool for mutational screening in this area. • Two novel mutations and seven missense mutations were identified on the F7 gene. [ABSTRACT FROM AUTHOR]

Background: Phenylketonuria (PKU) is an autosomal recessive disease resulting from a deficiency of the enzyme phenylalanine hydroxylase (PAH). Hyperphenylalaninemias (HPA) due to PAH deficiency are accompanied by a wide variety of clinical, biochemical, and molecular features. To identify and characterize pathogenic variants in the PAH gene and establish a correlation between genotype and biochemical phenotype in patients with PKU from state of Pará in the North Region of Brazil. Methods: All 13 exons of the PAH gene from 32 patients (21 PKU and 11 non‐PKU HPA) were amplified by PCR and submitted to DNA sequencing (Sanger). Biochemical data were obtained from the patients' medical records. Results: Molecular analysis identified 17 pathogenic variants and 3 nonpathogenic variants. The most frequent pathogenic variants were IVS10‐11G>A (7.9%), p. Arg261Gln (7.9%), p. Val388Met (6.3%) and p. Ile65Thr (4.7%). Was observed correlations and inconsistencies between genotype and biochemical phenotype. Conclusion: In PKU patients from state of Pará, North Region of Brazil, a heterogeneous mutation spectrum was revealed, in which the most frequent mutations are variants commonly observed in other Brazilian studies and in the region of the Iberian Peninsula. Molecular analysis performed identified 17 pathogenic mutations. The most frequent pathogenic variants were IVS10‐11G>A (7.9%), p. Arg261Gln (7.9%), p. Val388Met (6.3%) and p. Ile65Thr (4.7%). Was observed correlations and inconsistencies between genotype and phenotype. [ABSTRACT FROM AUTHOR]