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Congenital Muscular Dystrophies (CMD) are phenotypically and genotypically heterogenous disorders with a prevalence of 0.68 to 2.5/100,000, contributing to significant morbidity and mortality. We aimed to study the phenotype-genotype spectrum of genetically confirmed cases of CMD. This was retrospective & descriptive study done at a quaternary care referral centre in south India. Genetically confirmed cases of CMDs seen between 2010 to 2020 were recruited. Detailed clinical history, including pedigree, MRI brain/muscle, next generation sequencing results of 61 CMD cases were collected. Collagen VI-related dystrophy (COL6-RD) (36%) was the most common subtype with variants frequently seen in COL6A1 gene. Other CMDs identified were LAMA2-RD (26%), alpha-dystroglycan-RD (19%), LMNA-RD (8%), CHKB-RD (7%) and SEPN1-RD (3%). Similar to previous cohorts, overall, missense variants were common in COL-6 RD. Variants in triple helical domain (THD) of COL6-RD were seen in 11/22 patients, 5 of whom were ambulatory contrary to previous literature citing severe disease with these variants. However, our follow-up period was shorter. In the LAMA2-RD, 2/16 patients were ambulatory & all 16 carried truncating variants. Among dystroglycanopathies, FKRP-RD was the commonest. Milder phenotype of FKRP- RD was observed with variant c.1343C > T, which was also a recurrent variant in our cohort. p.Arg249Trp variant in LMNA-CMD associated with early loss of ambulation was also identified in 1/5 of our patients who expired at age 2.8 years. The current retrospective series provides detailed clinical features and mutation patterns of genetically confirmed cases of CMD from a single center in India. [ABSTRACT FROM AUTHOR]

Background Hereditary transthyretin amyloidosis (ATTRv) is an inherited, progressive, and fatal disease still largely underdiagnosed. Mutations in the transthyretin (TTR) gene cause the TTR protein to destabilize, misfold, aggregate, and deposit in body tissues, which makes ATTRv a disease with heterogeneous clinical phenotype.

Objective To summarize the clinical and genetic mutation characteristics of a family of early ‑ onset familial Alzheimer's disease (EOFAD) type 3 with spastic paraplegia as the first symptom. Methods and Results A 29 ‑ year ‑ old male patient with spastic paraplegia as the first symptom was admitted to Xuanwu Hospital, Capital Medical University on March 30, 2021. Head MRI showed multiple ischemic foci in bilateral subfrontal cortex and bilateral temporal lobes. Thoracic MRI showed mild atrophic changes. Follow‑up medical history showed the first symptom of the his father were similar and progressed rapidly, including spastic paralysis, speech disorders, dementia, and mental and behavioral abnormalities. The duration from onset to death was 7 years, showing a relatively malignant course. Whole exome sequencing (WES) revealed a missense mutation of PSEN1 gene exon 7 c.668A > G (p.Gln223Arg) in the patient. The results of Sanger sequencing showed the mother and sister of the patient did not carry this mutation, and it was speculated the mutation came from the father of the patient. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the above mutation was classified as likely pathogenic (PS3 + PM2 + PS4_Moderate). The patient was diagnosed with spastic paraplegia, and the family was diagnosed with EOFAD3. Conclusions A missense mutation of PSEN1 gene exon 7 c.668A > G (p.Gln223Arg) was identified, which was the pathogenic variant of this family, resulting in a rare EOFAD3 with spastic paraplegia as the first symptom, detailed family investigation combined with WES would help improve the efficiency of early diagnosis.

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Cytoplasmic T Lymphocyte Antigen-4 (CTLA-4) gene encodes for a glycoprotein, expressed on activated T-cells to transfer an inhibitory signal to control T-cell activation and proliferation. Techniques coupled with Real-time Polymerase Chain Reaction (PCR) and High-Resolution Melting Analysis (HRMA) were used to screen a missense signal peptide polymorphism (CTLA-4 + 49 A/G rs231775) in the Indian population to detect its association with Rheumatoid Arthritis (RA). Further, the resulting outcome was confirmed by Sanger's sequencing technique, and genotype frequencies were calculated. In eukaryotic cells, the M domain of the Signal Recognition Particle (SRP-54) recognizes the N-terminal region of the Signal Peptide (SP) sequence. SP directs the polypeptide chain into the Sec-61 translocon of the Endoplasmic Reticulum (ER) for further protein modification. As the Single Nucleotide Polymorphism (SNP) rs231775 lies in the signal peptide region of CTLA-4, an in-silico study was also performed to predict the mRNA stability and SP-SRP protein interaction. From the study, it was observed that the genotype frequency of rs231775 SNP G/G homozygous dominant was significantly higher in RA patients than G/A heterozygous dominant and A/A homozygous recessive conditions (Odd Ratio (OR) = 2.0862; 95 % Confidence Interval (C.I) = 1.2584 to 3.4584; Relative Risk (RR) = 1.8507; p = 0.0044). Moreover, the rs231775 SNP G allele frequency was higher in RA than the control group G = 0.407 (40.7 %) vs 0.32 (32 %). In silico approaches of Protein-Protein docking and Molecular Dynamics (MD) simulation reveal CTLA-4 rs231775 SNP (G allele) has destabilized the SP-SRP protein complex, which may affect the translocation of CTLA-4 nascent polypeptide chains into the ER via activating Regulation of Aberrant Protein Production (RAPP) pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Voltage-gated potassium (Kv) channels are integral to cellular excitability, impacting the resting membrane potential, repolarization, and shaping action potentials in neurons and cardiac myocytes. Structurally, Kv channels are homo or heterotetramers comprising four α-subunits, each with six transmembrane segments (S1-S6). Silent Kv (KvS), includes Kv5.1, Kv6.1-6.4, Kv8.1-8.2, and Kv9.1-9.3, they do not form functional channels on their own but modulate the properties of heteromeric channels. Recent studies have identified the Kv6.4 subunit as a significant modulator within heteromeric channels, such as Kv2.16.4. The Kv2.16.4 heteromer exhibits altered biophysical properties, including a shift in voltage-dependent inactivation and a complex activation. Current genetic studies in migraine patients have revealed a single missense mutation in the Kv6.4 gene. The single missense mutation, L360P is in the highly conserved S4-S5 linker region. This study aims to demonstrate the biophysical effects of the L360P mutation in Kv2.1 6.4 channels with a fixed 2:2 stoichiometry, using monomeric (Kv2.1/6.4) and tandem dimer (Kv2.1_6.4) configurations. Our findings suggest that the L360P mutation significantly impacts the function and regulation of Kv2.1/6.4 channels, providing insights into the molecular mechanisms underlying channel dysfunction in migraine pathology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neuronal ceroid lipofuscinosis type 10 (NCL10) is a rare progressive neurodegenerative disease associated with homozygous or compound heterozygous mutations in the CTSD gene encoding cathepsin D protein. It is classified as congenital, infantile, or juvenile NCL10 according to the age at onset of symptoms. Six cases of juvenile onset NCL10 (JNCL10) have been reported thus far in the literature. Herein, we report a nine-year-six-month-old girl with speech disorders, cognitive and motor decline, ataxia, and visual impairment. Developmental milestones were reported to be normal up to the age of 7 years. Biochemical and metabolic studies were normal. Electroencephalography showed intermittent generalized high-amplitude delta-wave activity during light sleep. Brain magnetic resonance imaging showed mild cerebellar atrophy. Whole-exome sequencing (WES) revealed a novel homozygous missense variant of c.1097G > A (p. Cys366Tyr) in the CTSD gene. Based on clinical, laboratory, and genetic findings, the patient was diagnosed with JNCL10. To the best of our knowledge, this is a novel variant and the first case reported in Turkey, and it is important in terms of broadening ethnicity and the spectrum of EEG findings., Competing Interests: Declarations. Ethical Approval: The authors confirm that the approval of an institutional review board was not required for this work. A written informed consent of the patient was obtained for the publication of his data. The authors have read the Journal’s position on issues involved in the ethical publication and affirm that this work is consistent with the guidelines. Informed Consent: Informed consent for the publication of this report was obtained from the patient’s parents in accordance with the national ethical regulation. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Recent discoveries have revealed that genetic variants in γ-aminobutyric acid type A (GABA A ) receptor subunits can lead to both gain-of-function (GOF) and loss-of-function (LOF) receptors. GABA A receptors, however, have a pseudosymmetrical pentameric assembly, and curiously diverse functional outcomes have been reported for certain homologous variants in paralogous genes (paralogous variants). To investigate this, we assembled a cohort of 11 individuals harboring paralogous M1 proline missense variants in GABRA1 , GABRB2 , GABRB3, and GABRG2. Seven mutations (α1 P260L , α1 P260S , β2 P252L , β3 P253L , β3 P253S , γ2 P282A , and γ2 P282S ) in α1β2/3γ2 receptors were analyzed using electrophysiological examinations and molecular dynamics simulations. All individuals in the cohort were diagnosed with developmental and epileptic encephalopathy, with a median seizure onset age of 3.5 mo, and all exhibited global developmental delay. The clinical data for this cohort aligned with established GABA A receptor GOF but not LOF cohorts. Electrophysiological assessments revealed that all variants caused GOF by increasing GABA sensitivity by 3- to 23-fold. In some cases, this was accompanied by LOF traits such as reduced maximal current amplitude and enhanced receptor desensitization. The specific subunit mutated and whether the mutation occurred in one or two subunits within the pentamer influenced the overall effects. Molecular dynamics simulations confirmed similar structural changes from all mutations, but with position-dependent asymmetry. These findings establish that paralogous variants affecting the 100% conserved proline residue in the M1 transmembrane helix of GABA A R subunits all lead to overall GOF traits. The unexpected asymmetric and mixed effects on receptor function have broader implications for interpreting functional analyses for multimeric ion-channel proteins., Competing Interests: Competing interests statement:P.C. is Executive Vice President, Research at the company Saniona in Denmark. The remaining authors declare no competing interests.

Background: Hereditary breast cancer is an autosomal dominant disease caused by variants in genes such as BRCA1/2, RAD51, ATM, BRIP1, and others. In a previous study using whole exome sequencing, we identified a germline variant of the LGR4 gene (rs34804482, NM_018490.5(LGR4):c.2531 A > G (p.Asp844Gly)) in a young Tuvan breast cancer patient (belonging to the Turkic-speaking tribes of Central Asia). The aim of this study was to determine the frequency of the variant of the LGR4 gene NM_018490.5(LGR4):c.2531 A > G (p.Asp844Gly) in ethnic groups of West Siberia using the PCR-RT method., Methods: The study involved 735 breast cancer patients from ethnic groups in Siberia, median age at diagnosis of 43 ± 15.6 years. The control group consisted of 727 healthy women from Siberia, median age of 43.05 ± 13.5 years., Results: The frequency of this variant (rs34804482) was 0.015 in Russian, 0.022 in Buryat, and 0.069 in Tuvan breast cancer patients. In Tuvan women with breast cancer, the frequency of the LGR4 gene variant was significantly higher than in Russian BC patients (0.069 versus 0.015, X 2  = 8.153, p = 0.005). The frequency of the LGR4 gene variant (rs34804482) in healthy Tuvan women was significantly higher than in healthy Russian women (0.066 versus 0.016, X 2  = 6.368, p = 0.012). The variant frequency in healthy Russians was close to that in Europeans (0.016 versus 0.0219)., Conclusions: We found no statistically significant differences in the rs34804482 frequency between breast cancer patients and healthy individuals in the ethnic groups studied. The highest frequency of this missense germline variant was observed among Tuvans., Competing Interests: Declarations. Ethical approval: This study was performed in line with the principles of the Declaration of Helsinki. The study was approved by the ethics committee of the Research Institute of Oncology of the Tomsk National Research Medical Center (Protocol No. 10 of September 24, 2021). Consent to participate: All the participants signed informed consent for study participation. Consent to publish: The manuscript is approved by all of the authors. Competing interests: The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

TP53 is mutated in 10 to 15% of cases of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and is associated with a previous exposure to cytotoxic therapy, complex cytogenetic abnormalities, and a poor prognosis. Recent data have established the importance of TP53-mutant allele status, the determination of which requires specific genetic testing. Compared with monoallelic disease, multihit TP53-mutant AML/MDS is associated with chromosomal abnormalities and decreased overall survival. Most TP53 mutations are missense mutations that localize to the DNA binding domain. Hot-spot mutations involving residues R175, Y220, G245, R248, R273, or R282 represent approximately 35% of all TP53 missense mutations in AML/MDS. There is evidence that these hot-spot mutations may have dominant negative or gain-of-function properties. Here we review this evidence and discuss its potential impact on patient outcomes and clinical management., (Copyright © 2024 by The American Society of Hematology.)

The tumor suppressor CHEK2 encodes the serine/threonine protein kinase CHK2 which, upon DNA damage, is important for pausing the cell cycle, initiating DNA repair, and inducing apoptosis. CHK2 phosphorylation of the tumor suppressor BRCA1 is also important for mitotic spindle assembly and chromosomal stability. Consistent with its cell-cycle checkpoint role, both germline and somatic variants in CHEK2 have been linked to breast and other cancers. Over 90% of clinical germline CHEK2 missense variants are classified as variants of uncertain significance, complicating diagnosis of CHK2-dependent cancer. We therefore sought to test the functional impact of all possible missense variants in CHK2. Using a scalable multiplexed assay based on the ability of human CHK2 to complement DNA sensitivity of Saccharomyces cerevisiae cells lacking the CHEK2 ortholog, RAD53, we generated a systematic "missense variant effect map" for CHEK2 missense variation. The map reflects known biochemical features of CHK2 while offering new biological insights. It also provides strong evidence toward pathogenicity for some clinical missense variants and supporting evidence toward benignity for others. Overall, this comprehensive missense variant effect map contributes to understanding of both known and yet-to-be-observed CHK2 variants., Competing Interests: Declaration of interests Unrelated to this work, F.P.R. is an investor in Ranomics Inc. and an investor in and advisor for SeqWell Inc. and BioSymetrics Inc. and has accepted grant funding from Alnylam Inc., Biogen Inc., Deep Genomics Inc., and Beam Therapeutics. He is also an investor and advisor in Constantiam Biosciences Inc., which provides related services. A.W., J.R., and B.J. are employed by and invested in Invitae. F.J.C. has received research support from GRAIL and consulting funding from AstraZeneca., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Lamins form a proteinaceous meshwork as a major structural component of the nucleus. Lamins, along with their interactors, act as determinants for chromatin organization throughout the nucleus. The major dominant missense mutations responsible for autosomal dominant forms of muscular dystrophies reside in the Ig fold domain of lamin A. However, how lamin A contributes to the distribution of heterochromatin and balances euchromatin, and how it relocates epigenetic marks to shape chromatin states, remains poorly defined, making it difficult to draw conclusions about the prognosis of lamin A-mediated muscular dystrophies. In the first part of this report, we identified the in vitro organization of full-length lamin A proteins due to two well-documented Ig LMNA mutations, R453W and W514R. We further demonstrated that both lamin A/C mutant cells predominantly expressed nucleoplasmic aggregates. Labeling specific markers of epigenetics allowed correlation of lamin A mutations with epigenetic mechanisms. In addition to manipulating epigenetic mechanisms, our proteomic studies traced diverse expressions of transcription regulators, RNA synthesis and processing proteins, protein translation components, and posttranslational modifications. These data suggest severe perturbations in targeting other proteins to the nucleus., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Background: Long QT syndrome is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by KCNH2 . Variant classification is difficult, often because of lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance. Here we sought to test whether variant-specific information, primarily from high-throughput functional assays, could improve both classification and cardiac event risk stratification in a large, harmonized cohort of KCNH2 missense variant heterozygotes., Methods: We quantified cell-surface trafficking of 18 796 variants in KCNH2 using a multiplexed assay of variant effect (MAVE). We recorded KCNH2 current density for 533 variants by automated patch clamping. We calibrated the strength of evidence of MAVE data according to ClinGen guidelines. We deeply phenotyped 1458 patients with KCNH2 missense variants, including QTc, cardiac event history, and mortality. We correlated variant functional data and Bayesian long QT syndrome penetrance estimates with cohort phenotypes and assessed hazard ratios for cardiac events., Results: Variant MAVE trafficking scores and automated patch clamping peak tail currents were highly correlated (Spearman rank-order ρ=0.69; n=433). The MAVE data were found to provide up to pathogenic very strong evidence for severe loss-of-function variants. In the cohort, both functional assays and Bayesian long QT syndrome penetrance estimates were significantly predictive of cardiac events when independently modeled with patient sex and corrected QT interval (QTc); however, MAVE data became nonsignificant when peak tail current and penetrance estimates were also available. The area under the receiver operator characteristic curve for 20-year event outcomes based on patient-specific sex and QTc (area under the curve, 0.80 [0.76-0.83]) was improved with prospectively available penetrance scores conditioned on MAVE (area under the curve, 0.86 [0.83-0.89]) or attainable automated patch clamping peak tail current data (area under the curve, 0.84 [0.81-0.88])., Conclusions: High-throughput KCNH2 variant MAVE data meaningfully contribute to variant classification at scale, whereas long QT syndrome penetrance estimates and automated patch clamping peak tail current measurements meaningfully contribute to risk stratification of cardiac events in patients with heterozygous KCNH2 missense variants., Competing Interests: None.

Purpose: The California National Primate Research Center contains a colony of rhesus macaques with a homozygous missense mutation in PDE6C (R565Q) which causes a cone disorder similar to PDE6C achromatopsia in humans. The purposes of this study are to characterize the phenotype in PDE6C macaques in detail to determine the onset of the cone phenotype, the degree to which the phenotype progresses, if heterozygote animals have an intermediate phenotype, and if rod photoreceptor function declines over time., Methods: We analyzed spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), and electroretinography (ERG) data from 102 eyes of 51 macaques (aged 0.25 to 16 years). Measurements of retinal layers as well as cone and rod function over time were quantitatively compared., Results: Homozygotes as young as 3 months postnatal showed absent cone responses on electroretinogram. Infant homozygotes had reduced foveal outer nuclear layer (ONL) thickness compared with wildtype infants (P < 0.0001). Over 4 years of study, no consistent changes in retinal layer thicknesses were found within 5 adult homozygotes. However, comparisons between infants and adults revealed reductions in foveal ONL thickness suggesting that cone cells slowly degenerate as homozygotes age. The oldest homozygote (11 years) had reduced rod responses. Heterozygotes could not be distinguished from wildtypes in any parameters., Conclusions: These data suggest that, like humans, macaque PDE6C heterozygotes are normal, and homozygote primates have absent cone function and reduced foveal ONL thickness from infancy. Cone photoreceptors probably degenerate over time and macular atrophy can occur. Rod photoreceptor function may wane in late stages.

Upon RNA virus infection, the signaling adaptor MAVS forms functional prion-like aggregates on the mitochondrial outer membrane, which serve as a central hub that links virus recognition to downstream antiviral innate immune responses. Multiple mechanisms regulating MAVS activation have been revealed; however, the checkpoint governing MAVS aggregation remains elusive. Here, we demonstrated that the palmitoylation of MAVS at cysteine 79 (C79), which is catalyzed mainly by the palmitoyl S-acyltransferase ZDHHC12, was essential for MAVS aggregation and antiviral innate immunity upon viral infection in macrophages. Notably, the systemic lupus erythematosus-associated mutation MAVS C79F was associated with defective palmitoylation, resulting in low type I interferon (IFN) production. Accordingly, Zdhhc12 deficiency apparently impaired RNA virus-induced type I IFN responses, and Zdhhc12-deficient mice were highly susceptible to lethal viral infection. These findings reveal a previously unknown mechanism by which the palmitoylation of MAVS is a checkpoint for its aggregation during viral infection to ensure timely activation of antiviral defense.

VPS13B/COH1 is the only known causative factor for Cohen syndrome, an early-onset autosomal recessive developmental disorder with intellectual inability, developmental delay, joint hypermobility, myopia, and facial dysmorphism as common features, but the molecular basis of VPS13B/COH1 in pathogenesis remains largely unclear. Here, we identify Sec23 interacting protein (Sec23IP) at the ER exit site (ERES) as a VPS13B adaptor that recruits VPS13B to ERES-Golgi interfaces. VPS13B interacts directly with Sec23IP via the VPS13 adaptor binding domain (VAB), and the interaction promotes the association between ERES and the Golgi. Disease-associated missense mutations of VPS13B-VAB impair the interaction with Sec23IP. Knockout of VPS13B or Sec23IP blocks the formation of tubular ERGIC, an unconventional cargo carrier that expedites ER-to-Golgi transport. In addition, depletion of VPS13B or Sec23IP delays ER export of procollagen, suggesting a link between procollagen secretion and joint laxity in patients with Cohen disease. Together, our study reveals a crucial role of VPS13B-Sec23IP interaction at the ERES-Golgi interface in the pathogenesis of Cohen syndrome., (© 2024 Du et al.)

Purpose: SDHA mutations are the most common cause of succinate dehydrogenase (SDH)-deficient GIST. Enhanced cancer surveillance of individuals carrying a known pathogenic germline SDHA mutation has the potential to detect early-stage tumors, allowing for improved patient outcomes. However, more than 95% of the >1,000 SDHA missense variants listed in ClinVar are variants of uncertain significance. Our ability to interpret the significance of SDHA variants must improve before genetic sequencing can be utilized to its full potential., Experimental Design: SDHA variants were introduced into a clonal SDHA-knockout cell line via Bxb1-mediated recombination. SDH activity and SDHA abundance were determined for each variant, and logistic regression analysis was used to derive functional evidence for clinical variant interpretation., Results: Our analysis revealed that cancer-associated SDHA missense variants can be clearly distinguished from noncancer variants according to the extent of SDH dysfunction caused. As such, SDH activity data can be used to predict cancer pathogenicity with strong performance metrics, exceeding those of computational prediction tools. From these data, we obtained functional evidence for clinical variant interpretation from 21 of 22 assayed variants of uncertain significance, with 19 in favor of cancer pathogenicity and two against pathogenicity. Lastly, simulating the addition of our functional evidence with limited preexisting evidence allowed for 18 of 22 variants to be reclassified., Conclusions: We describe a novel pipeline for investigating the functional consequences of SDHA missense variants. In total, we characterized 72 variants, developed criteria for obtaining functional evidence, and demonstrated the potential of this evidence for clinical variant interpretation., (©2024 American Association for Cancer Research.)

HLA-C*03:656 differs from HLA-C*03:04:01:02 by a single missense nucleotide substitution in codon 342 in exon 7., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare, autosomal recessive condition characterized by fibroblast growth factor 23 signaling pathway dysregulation, hyperphosphatemia and ectopic calcifications (which manifest as joint motion limitations), inflammatory bony pain, and disability. Given the rarity and multiorgan involvement of HFTC, a multidisciplinary approach including Dermatology, Ophthalmology, Dentistry, Nephrology, Endocrinology, Rheumatology, and Genetics is necessary for diagnosis and treatment. We present a multidisciplinary diagnostic and treatment approach for a patient with HFTC due to a GALNT3 gene mutation with unique imaging highlighting the extent of calcinosis seen in HFTC. In this case study, a 34-year-old female patient found to have HFTC was first evaluated at an outpatient academic dermatology center in October 2020 and studied for 1 year. Genetic testing revealing a homozygous c.1319C > A variant in GALNT3 predicted to result in a missense mutation p.Ala440Glu. HFTC should be considered for patients presenting with diffuse calcinosis cutis-like features, and a multidisciplinary evaluation should be pursued.

BRAF V600E mutations are frequently found in histiocytic/dendritic cell neoplasms such as Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH), but few reports have also described BRAF mutations in Rosai-Dorfman disease (RDD), and even these cases may predominantly represent mixed histiocytosis. BRAF mutations have been studied in histiocytic/dendritic cell neoplasms and described to be associated with increased risk of relapse and long-term consequences, but few studies have examined BRAF V600E mutation in RDD, which is recognized as a neoplasm given the high frequency of MAPK pathway alterations. Here, we report a case of BRAF V600E-mutated RDD in a patient who presented with generalized lymphadenopathy. During our evaluation of this patient, we also found expression of PD-L1 in neoplastic histiocytes. During our review period, only few cases of RDD reported to harbor BRAF mutation or were evaluated for the expression of PDL1 by neoplastic cells. Given the potential challenges in distinguishing RDD from other histiocytic/dendritic cell neoplasms, including mixed histiocytosis with similar clinicopathological manifestations, we will discuss the current state of knowledge regarding the frequency and clinical impact of BRAF V600E in RDD, as well as the role of BRAF mutations in RDD pathogenesis. Distinction of BRAF V600E mutated histiocytic/dendritic cell neoplasms requires consideration of distinctive histopathological and immunophenotypic findings in appropriate clinical and radiologic setting. Given the increasing use of BRAF inhibitors as well as checkpoint blockade inhibitors to treat a number of cancers, we will discuss the clinical implications of the presence of BRAF V600E mutation and PD-L1 expression in RDD., Competing Interests: Declarations. Ethical approval: For this type of study, formal consent is not required. Informed consent: For this type of study, informed consent is not required. Consent for publication: Consent for publication was obtained for every individual person’s data included in the study. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Background and Aims: Retinitis pigmentosa (RP) is a hereditary retinal disorder that gradually leads to vision loss due to photoreceptor cell degeneration. This study aims to investigate the clinical features and genetic underpinnings of RP within a large Iranian family. Our focus centered on mutations in the NR2E3 gene, which plays a critical role in the development and maintenance of the retina., Methods: Twenty-five family members showed symptoms of RP, and fourteen of them underwent clinical examinations conducted by geneticists and ophthalmologists. The DNA samples of five individuals diagnosed with RP from the family were subjected to whole-exome sequencing (WES) as part of the study. The candidate variant identified through WES was subsequently confirmed using bidirectional sequencing in additional family members. Additionally, in silico analysis, including molecular modeling, protein-protein docking, and molecular dynamics simulation (MD), was employed to assess potential pathogenic effects associated with the candidate variants., Results: Ophthalmic examination revealed night blindness, which is a common symptom among affected individuals. Genetic analysis identified a homozygous missense variant (c.934G>A/p.R311Q) in NR2E3 exon 6, which co-segregates with other affected family members. Furthermore, molecular docking analysis indicated potential disruption in the binding affinity between NR2E3 and NR1D1 proteins. In-depth, molecular dynamics analysis, considering parameters such as RMSD, RMSF, and hydrogen bonding, revealed notable differences between normal and mutant protein complexes., Conclusion: Exploring the molecular interaction between NR2E3 and NR1D1 provides new insights into the pathogenic mechanism of the p.R311Q mutation in RP., (© 2024 The Author(s). Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

A homozygous E40K mutation in the gene coding canine Cu/Zn-superoxide dismutase (cSOD1) causes degenerative myelopathy (DM) in dogs. A pathological hallmark of DM with the cSOD1 mutation is the aggregation of mutant cSOD1 proteins in neurons. The amino acid substitution E40K disrupts a salt bridge between Glu40 and Lys91 and is considered to destabilize the native state of cSOD1; however, the mechanism by which mutant cSOD1 aggregates remains unclear. Here, we show that mutant cSOD1 losing a copper and zinc ion forms oligomers crosslinked via disulfide bonds. The E40K substitution was found to result in the increased solvent exposure of the Cys7 side chain, which then attacked the disulfide bond (Cys57-Cys146) in cSOD1 to form disulfide-linked oligomers. We also successfully prevented the Cys7 exposure and thus the oligomerization of mutant cSOD1 by a fragment antibody that specifically recognizes the region around the mutation site. The fragment antibody covered the β-plug region, reinforcing the interactions compromised by the E40K substitution and thus contributing to the maintenance of the structural integrity of the β-barrel core of cSOD1. Taken together, we propose that the Cys7 exposure in cSOD1 upon the salt bridge disruption plays a central role in the aggregation mechanism of DM-associated mutant cSOD1., (© 2024 The Author(s). Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Objective: The purpose of this study was to determine the molecular basis of a Chinese family with factor XI (FXI) deficiency., Methods: The qRT-PCR was used to detect the transcription of F11 mRNA in transfected cells. ELISAs and western blot were used to detect the expression of FXI protein in culture media and lysates., Results: Genetic analysis revealed that the proband carried a heterozygous nonsense mutation c.1107C>A (p.Tyr351stop) in exon 10 and a heterozygous missense mutation c.1562A>G (p.Tyr503Cys) in exon 13. The expression study revealed that p.Tyr351stop mutation resulted in the degradation of F11 mRNA. The p.Tyr503Cys mutation, however, had no effects on biosynthesis and secretion of FXI protein, but it had affected the catalytic activity of FXI., Conclusion: The inherited FXI deficiency of this family is related to nonsense mutation p.Tyr351stop and missense mutation p.Tyr503Cys., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Ocular coloboma (OC) is a congenital disorder caused by the incomplete closure of the embryonic ocular fissure. OC can present as a simple anomaly or, in more complex forms, be associated with additional ocular abnormalities. It can occur in isolation or as part of a broader syndrome, exhibiting considerable genetic heterogeneity. Diagnostic yield for OC remains below 30%, indicating the need for further genetic exploration. Mutations in the Wnt receptor FZD5, which is expressed throughout eye development, have been linked to both isolated and complex forms of coloboma. These mutations often result in a dominant-negative effect, where the mutated FZD5 protein disrupts WNT signaling by sequestering WNT ligands. Here, we describe a case of syndromic bilateral OC with additional features such as microcornea, bone developmental anomalies, and mild intellectual disability. Whole exome sequencing revealed a homozygous rare missense variant in FZD5. Consistent with a loss-of-function effect, overexpressing of fzd5 mRNA harboring the missense variant in zebrafish embryos does not influence embryonic development, whereas overexpression of wild-type fzd5 mRNA results in body axis duplications. However, in vitro TOPFlash assays revealed that the missense variant only caused partial loss-of-function, behaving as a hypomorphic mutation. We further showed that the mutant protein still localized to the cell membrane and maintained proper conformation when modeled in silico, suggesting that the impairment lies in signal transduction. This hypothesis is further supported by the fact that the variant affects a highly conserved amino acid known to be crucial for protein-protein interactions., Competing Interests: Declarations Competing interests The authors declare no competing interests. Rights retention statement This research was funded in part, by the Wellcome Trust [Seed Award in Sciences 213928/Z/18/Z to FC]. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission., (© 2024. The Author(s).)

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to reduced α-galactosidase (α-Gal A) activity. Current treatments, like enzyme replacement, have limitations affecting efficacy and patient outcomes. CRISPR/Cas9 genome editing tools may offer the potential to develop therapeutic strategy via correcting GLA mutations. In this study, we diagnosed a female FD patient with a missense mutation in exon 1 of the GLA gene (c.146G > A, p.R49H). Bioinformatic predictions and biochemical analyses in GLA-knockout cells revealed that this mutation significantly reduced α-Gal A stability and activity, confirming its pathogenicity. To correct this, we used adenine base editing. The mutation, along with a nearby bystander A, was efficiently edited by the traditional N-terminal adenine base editor. To avoid unwanted bystander editing, we developed a series of domain-inlaid base editors with the aim of narrowing editing window. The most effective variant, with deaminase inserted between the 947th and 948th residues of the RUVC3 domain, was further optimized by modifying linker rigidity. These adjustments shifted the editing window, eliminating bystander editing. Our findings clarify the pathogenic nature of a novel GLA mutation and demonstrate the potential of a customized base editor for therapeutic application in FD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Genetic studies in mice have shown that the zinc finger transcription factor BCL11B has an essential role in regulating early T cell development and neurogenesis. A de novo heterozygous missense BCL11B variant, BCL11B N441K , was isolated from a patient with T cell deficiency and neurological disorders. Here, we show that mice harboring the corresponding Bcl11b N440K mutation show the emergence of natural killer (NK)/group 1 innate lymphoid cell (ILC1)-like NKp46 + cells in the thymus and reduction in TBR1 + neurons in the neocortex, which are observed with loss of Bcl11a but not Bcl11b. Thus, the mutant BCL11B-N440K protein interferes with BCL11A function upon heterodimerization. Mechanistically, the Bcl11b N440K mutation dampens the interaction of BCL11B with T cell factor 1 (TCF1) in thymocytes, resulting in weakened antagonism against TCF1 activity that supports the differentiation of NK/ILC1-like cells. Collectively, our results shed new light on the function of BCL11A in suppressing non-T lymphoid developmental potential and uncover the pathogenic mechanism by which BCL11B-N440K interferes with partner BCL11 family proteins., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Premature ovarian insufficiency (POI) is one of the leading causes of female infertility. To date, the genetic etiology of POI has been elucidated in approximately 20-25% of the total cases. The human zona pellucida (ZP) plays an important role in the organization and differentiation of granulosa cells, follicle formation, and sperm recognition. Mutations in ZP1, ZP2, and ZP3 have been reported to cause female infertility due to oocyte degeneration, empty follicle, or in vitro fertilization failure. In this study, we identified three novel missense mutations in ZP3 (NM&#95;001110354.2): c.643G > A (p.Asp215Asn), c.215 C > T (p.Thr72Ile), and c.152T > C (p.Leu51Pro) in three sporadic Han Chinese POI patients through whole-exome sequencing. These variants are absent from population databases and were predicted to be deleterious by multiple in silico tools. Structure prediction analysis showed that the affected amino acid altered the ZP3 protein structure. Western blot further confirmed that these ZP3 variants reduced the expression and secretion of ZP components. In summary, this study reports three novel deleterious variants in ZP3 associated with POI, thereby broadening the mutation spectrum of ZP3 in POI patients., Competing Interests: Declarations. Ethical Approval: Declaration of Helsinki and approved by the institutional review board of the center participating in this study. All patients gave their signed informed consent for this study. Consent for Publication: Not applicable. Conflict of Interest: The authors declare no conflict of interest., (© 2024. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Objective: N-methyl-D-aspartate receptors are glutamate-gated ion channels that play a crucial role in brain function. Numerous inherited or de novo variants in the GRIN2A gene, encoding the GluN2A subunit of the receptor, have been identified in patients with epilepsy. In addition, it is worth noting that GRIN2A variants exhibit a strong correlation with epilepsy-aphasia syndromes, a group of age-dependent epileptic, cognitive, and language disorders with a characteristic electroencephalographic pattern., Methods: Whole exome sequencing was conducted in enrolled patients with epilepsy-aphasia syndromes, and GRIN2A variants were screened. The conservation of substituted residues, conformational changes of mutant subunits, and in silico predictions of pathogenicity were thoroughly assessed in our study. Functional alterations of the variants were examined using whole-cell voltage-clamp current recordings while the relative surface expression levels of subunit proteins were assessed via immunofluorescence assays. A summary of previously published GRIN2A missense variants was conducted to investigate the genotypic-phenotypic-functional correlations., Results: Two missense GRIN2A variants (c. 2482A >G/p. M828V, c. 2627 T >C/p. I876T) were identified, which are located in the transmembrane helix M4 and C-terminus domain of the GluN2A subunit, respectively. Both variants exhibited reduced current density of NMDARs and surface/total expression levels of GluN2A subunits, while M828V showed a decreased extent of desensitization as well. A further summary of the previously reported GRIN2A variants demonstrated that more variable phenotypes were observed for variants situated in the C-terminus domain or those with loss-of-function effects., Significance: Our study expands the phenotypic and functional range of GRIN2A-related disorders. In order to optimally establish the domain-function-phenotype correlations in GRIN2A variants, it is imperative to gather a more extensive set of clinical and functional data., Plain Language Summary: This study has identified two genetic variants of the GRIN2A gene in patients with epilepsy-aphasia syndrome. We assess the variants' harmfulness through a variety of functional experiments, including evaluating the expression level of the mutated protein and the resulting changes in electrophysiological activities. Also, we reviewed previously published papers about GRIN2A variants in epilepsy to learn more about the correlations between their locations, functional changes, and clinical manifestations., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

(Charcot-Marie-Tooth disease (CMT) is a genetic disorder affecting peripheral nerves. The human induced pluripotent stem cell (iPSC) line JUCTCi018-A was created using dermal fibroblasts from a Charcot-Marie-Tooth disease type 2EE (CMT2EE) patient with a homozygous missense mutation in the MPV17 gene (c. 122G > A, p.Arg41Gln). These fibroblasts were reprogrammed using Sendai viruses that encoded OCT4, SOX2, KLF4, and c-MYC reprogramming factors. The iPSCs demonstrated normal morphology and karyotype, expressed pluripotency markers, and the ability to differentiate into the three germ layers. This iPSC line is valuable for investigating the mechanisms underlying CMT2EE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

CAD, the multi-enzymatic protein essential for initiating the de novo biosynthesis of pyrimidine nucleotides, forms large hexamers whose structure and function are not fully understood. Defects in CAD cause a severe neurometabolic disorder that is challenging to diagnose. We developed a cellular functional assay to identify defective CAD variants, and in this study, we characterized five pathogenic missense mutations in CAD's dihydroorotase (DHO) and aspartate transcarbamoylase (ATC) domains. All mutations impaired enzymatic activities, with two notably disrupting the formation of DHO dimers and ATC trimers. Combining crystal structures and AlphaFold predictions, we modeled the hexameric CAD complex, highlighting the central role of the DHO and ATC domains in its assembly. Our findings provide insight into CAD's stability, function, and organization, revealing that correct oligomerization of CAD into a supramolecular complex is required for its function in nucleotide synthesis and that mutations affecting this assembly are potentially pathogenic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The CCDC22 gene plays vital roles in regulating the NF-κB pathway, an essential pathway for neuroinflammation, neurodevelopment, and epileptogenesis. Previously, variants in CCDC22 were reported to be associated with intellectual disability. This study aimed to explore the association between CCDC22 and epilepsy., Methods: Trios-based whole-exome sequencing (WES) was performed in a cohort of patients with epilepsy of unknown cause recruited from the China Epilepsy Gene 1.0 Project. Damaging effects of variants were analysed using protein modelling., Results: Hemizygous missense CCDC22 variants were identified in three unrelated cases. These variants had no hemizygous frequencies in controls. All missense variants identified in this study were predicted to be "damaging" by multiple in silico tools and to alter the hydrogen bonds with surrounding residues and/or protein stability. The three patients presented with focal epilepsy of varying severity, including one with refractory seizures and focal cortical dysplasia (FCD) and two with seizures responding to antiseizure medicine. Notably, the variant associated with the severe phenotype was located in the coiled-coil domain and predicted to alter hydrogen bonding and protein stability, whereas the two variants associated with mild epilepsy were located outside functional domains and had moderate molecular alterations. Analysis of spatiotemporal expression indicated that CCDC22 was expressed in brain subregions with three peaks in the fetal stage, infancy, and early adulthood, especially in the fetal stage, explaining the occurrence of developmental abnormities., Significance: CCDC22 variants are potentially associated with X-linked focal epilepsy and FCD. The molecular subregional effects supported the occurrence of FCD., Competing Interests: Declaration of competing interest All the authors declare that there are no conflicts of interest., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

This study investigates the rs547238576 (R150S) missense variant in the oxytocin receptor (OXTR) gene, previously observed through screening of rare variants in Japanese individuals with autism spectrum disorders (ASD). Contrary to the anticipated loss-of-function, R150S exhibits gain-of-function effects, enhancing oxytocin (OXT) sensitivity, ligand-binding affinity, and OXT-induced Ca 2+ mobilization in vitro. This suggests R150S may alter OXT signaling, potentially contributing to the excitatory/inhibitory imbalance seen in ASD and other psychiatric disorders. Our findings underscore the significance of genetic variations in OXTR on functional activity and highlight the necessity for population-specific genetic study and in vitro analysis to elucidate genetic susceptibilities to neuropsychiatric conditions., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cardiac muscle α-actin is a key protein of the thin filament in the muscle sarcomere that, together with myosin thick filaments, produce force and contraction important for normal heart function. Missense mutations in cardiac muscle α-actin can cause hypertrophic cardiomyopathy, a complex disorder of the heart characterized by hypercontractility at the molecular scale that leads to diverse clinical phenotypes. While the clinical aspects of hypertrophic cardiomyopathy have been extensively studied, the molecular mechanisms of missense mutations in cardiac muscle α-actin that cause the disease remain largely elusive. Here we used cryo-electron microscopy to reveal the structures of hypertrophic cardiomyopathy-associated actin mutations M305L and A331P in the filamentous state. We show that the mutations have subtle impacts on the overall architecture of the actin filament with mutation-specific changes in the nucleotide binding cleft active site, interprotomer interfaces, and local changes around the mutation site. This suggests that structural changes induced by M305L and A331P have implications for the positioning of the thin filament protein tropomyosin and the interaction with myosin motors. Overall, this study supports a structural model whereby altered interactions between thick and thin filament proteins contribute to disease mechanisms in hypertrophic cardiomyopathy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Laureano J. Kamiya and colleagues have identified two novel missense variants (Gly168Arg and Gly168Glu) in the RUNX1 gene. These variants, identified in two unrelated families with familial platelet disorder with a predisposition to acute myeloid leukaemia (FPD/AML) phenotype, were initially classified as variants of uncertain significance (VUS). However, functional studies of RUNX1 target genes enabled their reclassification as likely pathogenic. The findings highlight Gly168 as a new mutation hotspot in RUNX1, providing important insights for genetic counselling and leukaemia monitoring. The study emphasizes the necessity for continuous updates to diagnostic guidelines and data sharing among laboratories to improve the classification and interpretation of genetic variants. Commentary on: Kamiya et al. Two novel families with RUNX1 variants indicate glycine 168 as a new mutational hotspot: Implications for FPD/AML diagnosis. Br J Haematol 2024; 205:2327-2337., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Hereditary sensory and autonomic neuropathies (HSAN) represent a group of genetic diseases affecting the peripheral nervous system. In humans, at least 16 loci have been associated with the disorder but do not explain the disease origin of all patients. In dogs, similar conditions have been documented for decades in various breeds with a severe impact on life quality and are often referred to as acral mutilation syndrome (AMS). Causal variants in three genes have been identified to date, suggesting larger genetic heterogeneity in the dog population. Our aim was to explain the genetic etiology of an early-onset HSAN/AMS in a purebred German Spitz. The affected dog showed progressive loss of pain sensation in the distal extremities, which led to intense licking, biting, and self-mutilation of digits and paw pads. Whole-genome sequencing identified a single candidate causal variant on chromosome 4 in the RETREG1 gene (c.656C>T, p.Pro219Leu). This missense variant was previously recognized as deleterious in a mixed breed dog family with similar clinical signs. Haplotype analyses and targeted genotyping revealed a likely German Spitz ancestry of these mixed breed dogs. Further screening of an extensive cohort of ~900 000 dogs of various breeds hinted at the variant allele origin in the German Spitz breed. Disruption of RETREG1 inhibits endoplasmic reticulum turnover and leads to neuron degeneration. Our findings provide evidence that this variant underlies the recessive form of HSAN/AMS in the German Spitz and support the use of whole-genome sequencing-based veterinary precision medicine for early diagnosis and prevention via a genetic test., (© 2024 The Author(s). Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.)

Acromelanism is a form of albinism observed in several vertebrate species. In mammals, acromelanism is known to be caused by mutations in the tyrosinase gene (TYR) that induce a temperature-sensitive behavior of melanin synthesis, resulting in a characteristic hair color gradient. In birds, several phenotypes consistent with acromelanism have been reported, but their genetic basis remains unknown. This study aimed to identify the genetic basis of an acromelanistic phenotype in domesticated canaries known as pearl and test whether it is caused by the same molecular mechanism described for mammals. To do this, we compared the genomes of pearl and non-pearl canaries and searched for potentially causative genetic mutations. Our results suggest that the pearl phenotype is caused by a mutation in the TYR gene encoding a TYR-P45H missense substitution. Our findings further suggest that reports of acromelanism in other bird species might be explained by TYR mutations., (© 2024 Stichting International Foundation for Animal Genetics.)

Correct interpretation of the pathogenicity of germline RUNX1 variants is essential for FPD/AML diagnosis, clinical management and leukaemia surveillance. We report two families with clear FPD/AML phenotypic features harbouring missense variants at RHD critical residue Gly168. Although classified as of unknown significance (VUS) by RUNX1-specific curation guidelines, these variants should rather be considered likely pathogenic, as supported by computational tools, structural modelling and dysregulated platelet expression of RUNX1-targets, adding Gly168 among amino acids currently recognised as mutational hotspots. Our data could help reduce the number of variants classified as VUS, providing evidence for updating RUNX1 guidelines, thus improving FPD/AML diagnosis., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Retinitis pigmentosa (RP) is a genetically heterogeneous disease. RP 79 has been associated with heterozygous variants of hexokinase 1 (HK1). Only two missense HK1 variants have been reported in 11 families., Objective: To discover the molecular pathogenic mechanism of RP and validate the biological harm of HK1 through in vitro experiments., Methods: We conducted a genetic analysis of a 3-year-old female patient with RP and her family. We also evaluated the ocular phenotypes caused by HK1 (the identified variant). Peripheral blood samples were collected from the patient, her parents, and her brother, and trio whole-exome sequencing was performed. A protein structure analysis was performed to assess the functional impact of the variant, and a mutant plasmid was constructed for the quantitative polymerase chain reaction (qPCR) and western blot (WB) analysis of the effects of the variant on transcription and protein translation., Results: The patient harbored the NM&#95;000188.3: c.613del (p.Ala205Leufs*3) variant, which is a heterozygous variant of HK1. Sanger sequencing confirmed the presence of this variant in the patient; however, the patient's parents and brother had the wild-type variant. The protein structure analysis indicated that the variant resulted in a truncated protein caused by premature termination of amino acid coding. The qPCR results indicated that the variant may not have affected the transcription process. However, the WB analysis demonstrated that the mutant HK-1 protein was not expressed and that the wild-type group exhibited normal expression., Conclusions: Our patient had a loss-of-function (LoF) variant of HK1, which may be the genetic cause of typical features of RP that are observed at an early age. These findings expand the spectrum of HK1 variants and phenotypes and suggest that LoF variants of HK1 may represent a specific pathogenic mechanism of RP., Competing Interests: Declarations. Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approved by the Ethics Committee of the Xi’an People’s Hospital (Approval No.: KJLL-Z-K-2023072). Informed consent: Consent to publish has been obtained from the guardians of all involved the child. Competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024. The Author(s) under exclusive licence to The Genetics Society of Korea.)

Advocacy support groups grow into national and international organizations, but they all begin with personal experiences. As the parents to a newly diagnosed two-year-old son with Myhre syndrome, my husband and I were overwhelmed with the journey ahead. Thanks to networking, primarily through social media, we located other families living with Myhre syndrome and were quickly immersed in the challenges and joy of this community. Myhre syndrome, caused by pathogenic missense variants in SMAD4, is a rare connective tissue disease characterized by short stature, hearing loss, neurodevelopmental challenges, and fibroproliferation. This personal essay, written with physician partners, describes the development of a global advocacy group for patients with Myhre syndrome. I have the honor of serving as the founding Executive Director and reflect proudly on the great strides that our marvelous support group has made. We empower the global community impacted by this rare condition by providing meaningful and accessible data, educational opportunities, and connections with others going through similar experiences. Utilizing the expertise of our Board of Directors and my corporate expertise, we discuss how we have been able to elevate our ultra-rare community into a broader, more comprehensive network., (© 2024 Wiley Periodicals LLC.)

Pathogenic SOX11 variants have been associated with intellectual developmental disorder with microcephaly, and with or without ocular malformations or hypogonadotropic hypogonadism (HH) (IDDMOH, OMIM # 615866). In this article, we report seven new patients with de novo SOX11 variants. Five of the variants are missense, one nonsense, and one whole-gene deletion, most of them are novel variants. The main clinical features included neurodevelopmental delay (7/7) and intellectual disability (5/7), autism/attention deficit hyperactivity disorder (5/7), microcephaly (4/7), short stature (4/7), hypotonia (4/7), and clinodactyly of the 5th fingers (5/7). HH was confirmed in two female patients with primary amenorrhea, nonvisualized/prepubertal size of the uterus, and nonvisualized ovaries. Two of the male patients presented with micropenis, two had cryptorchidism, and one had decreased testicular size, which are suggestive findings of HH. This article contributes to the clinical characterization of patients with SOX11 variants and supports the role of this gene in HH., Competing Interests: Competing interests: HZE and MS are employees of GeneDx, LLC. The other authors declare no competing interests. Ethical approval: Written consent for clinical data collection was given by legal guardians. Ethical approval was obtained by the respective institutional research ethics board for each individual., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

Bi-allelic pathogenic variants in GRID2 have been initially associated to an autosomal recessive form of spinocerebellar ataxia, namely SCAR18. Subsequently, few monoallelic cases have been described. Here we present a new subject harboring a novel de novo heterozygous GRID2 missense variant presenting with progressive ataxia together with cerebellar atrophy and, for the first time, alpha-fetoprotein (AFP) elevation. We retrospectively collected data of the patient followed at our clinic. Genetic analysis was performed through clinical exome sequencing with an in-house in-silico ataxia-related genes panel. Variant effect prediction was performed through in silico modeling. The patient had normal psychomotor development except for mild fine and gross motor impairment. In adolescence, he started presenting dysarthria and progressive ataxia. Blood tests showed significant AFP elevation. Brain MRI showed cerebellar atrophy mainly involving the vermis. The novel de novo heterozygous GRID2 (c.1954C>A; p.Leu652Ile) missense variant was disclosed. This variant is located within a highly conserved site with low tolerance to variation and it is predicted to cause protein structure destabilization. GRID2 expression appears to be influenced by other genes related with ataxia and AFP elevation, like ATM and APTX, suggesting a possible shared mechanism. This additional patient increases the scarce literature and genotypic spectrum of the GRID2-related ataxia and evidences a fairly homogeneous phenotype of ataxia with oculomotor abnormalities for the autosomal-dominant form. Alfa-fetoprotein elevation is a novel finding in this condition and this data must be confirmed in larger case-series to definitively state that GRID2-related ataxia can be included among ataxias with AFP increase., Competing Interests: Declarations. Institutional Review Board Statement: Submission of the manuscript has been approved by our Institution (approval number RAP-2024-0003). Informed Consent Statement: Patient’s parents have signed the written informed consent for genetic analyses and for participation in research study. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Bartter syndrome type 1, an autosomal recessive genetic disorder, is caused by pathogenic loss-of-function variants in the SLC12A1 gene. It is characterized by metabolic alkalosis and prenatal-onset polyuria leading to polyhydramnios., Methods: We identified pathogenic gene in a 12-day-old newborn boy with Bartter syndrome type 1 using whole-exome sequencing. Sanger sequencing validated the identified variants. A minigene assay was performed to investigate the effect of a novel splice site variant on pre-mRNA splicing., Results: We found a compound heterozygous variants in the SLC12A1 gene, consisting of a known pathogenic missense mutation (NM&#95;000338: c.769 G>A; p.Gly257Ser) and a novel splice site variant (c.1684+1 G>A). In silico predictions and an in vitro minigene splicing assay demonstrated that the splicing variant c.1684+1 G>A abolished a consensus splice donor site of SLC12A1 intron 13, resulting in complete exon 13 skipping, translational frameshift, and premature termination codon, ultimately leading to loss of SLC12A1 function., Conclusion: Using a cell-based in vitro assay, we revealed the aberrant effect of the pathogenic splicing variant SLC12A1 c.1684+1 G>A on pre-mRNA splicing. Our findings expand the gene mutation spectrum of Bartter syndrome type 1, providing a basis for genetic diagnosis and the development of genetic medicines., (© 2024 Asian Pacific Society of Nephrology.)

Purpose: Pathogenic variants in the CLDN19 gene are responsible for Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC) with ocular pathology (MIM *248190). Our objective was to delineate the ophthalmological and genetic manifestations of a patient with FHHNC and a pathogenic variant in CLDN19 ., Case Report: A 25-year-old woman presented with renal involvement and a best-corrected visual acuity of 20/25 in the right eye and finger-counting ability in the left eye. The patient exhibited high myopia, convergent strabismus, and chorioretinal atrophic plaques in the perifoveal and peripapillary areas. We conducted a comprehensive ophthalmological examination, including refraction, fundoscopy, color and autofluorescence retinography, optical coherence tomography, and electrophysiology tests. Additionally, next-generation sequencing was performed using Illumina NextSeq500. We identified a homozygous missense variant, c.59G>A p.Gly20Asp, in the CLDN19 gene as the cause of renal and ocular manifestations., Conclusion: FHHNC is associated with various ocular alterations. The unique retinal disorders described in this article suggest a more favorable visual prognosis compared to those previously reported in the literature. Determining the phenotypic diversity of this disease may aid in the diagnosis and management of future cases.

Background: Cherubism is most commonly caused by rare heterozygous gain-of-function (GOF) missense variants in SH3BP2, which appear to signal through phospholipase C gamma 2 (PLCG2) to cause excessive osteoclast activity leading to expansile lesions in facial bones in childhood. GOF variants in PLCG2 lead to autoinflammatory PLCG2-associated antibody deficiency and immune dysregulation (autoinflammatory PLAID, or PLAID-GOF), characterized by variably penetrant autoinflammatory, autoimmune, infectious, and atopic manifestations. Cherubism has not been reported in PLAID to date., Objective: We determined whether GOF PLCG2 variants may be associated with cherubism., Methods: Clinical, laboratory, and genomic data from 2 patients with cherubism and other clinical symptoms observed in patients with PLCG2 variants were reviewed. Primary B-cell receptor-induced calcium flux was assessed by flow cytometry., Results: Two patients with lesions consistent with cherubism but no SH3BP2 variants were found to have rare PLCG2 variants previously shown to be GOF in vitro, leading to increased primary B-cell receptor-induced calcium flux in one patient's B cells. Variable humoral defects, autoinflammatory rash, and other clinical and laboratory findings consistent with PLAID were observed as well., Conclusion: GOF PLCG2 variants likely represent a novel genetic driver of cherubism and should be assessed in SH3BP2-negative cases. Expansile bony lesions expand the phenotypic landscape of autoinflammatory PLAID, and bone imaging should be considered in PLAID patients., Competing Interests: Disclosure statement Supported by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (R24 AI 17745 to J.D.M.), and the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Z01-AR041198 to M.J.O.). Disclosure of potential conflict of interest: J. D. Milner is on the scientific advisory board for Blueprint Medicine and receives grant funding from Pharming. W. K. Chung is the on the board of directors of Rallybio and Prime Medicine. S. B. Eisig is cofounder of Epibone. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

A recently described type of neonatal diabetes mellitus is caused by mutations in the YIPF5 gene and is combined with manifestations from the central nervous system, including developmental delay, epilepsy, and microcephaly. The molecular pathophysiology behind this phenotype involves the breakdown of the endoplasmic reticulum stress response due to the loss of protein folding capacity. This results in overt diabetes present from very early in life. Herein, we describe a patient with a newly reported variant in the YIPF5 gene, who presented with short events of severe hyperglycemia, induced by the stress of common illnesses, which completely resolved after recovery. We discuss the nature of transient hyperglycemia in the context of the YIPF5 gene variant and compare this phenotype with the previously described cases., (© 2024. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

Background: High myopia is a major cause of visual impairment, and genetic factors play crucial roles in the pathogenesis. We performed this study to identify candidate genes for the development of high myopia in a four-generation Chinese family with myopia., Methods: All family members with myopia and 100 healthy participants were included in this study. Data were obtained on demographics, disease history, and ocular examination results. We performed whole exome sequencing of the genomic DNA and Sanger sequencing to verify the variants. Functional analyses of the variant were performed using software programmes., Results: Nine of thirteen family members were found to have high myopia, amongst which two members were also diagnosed keratoconus. A missense variant in the keratin 12 gene (KRT12, p.Val410Gly) was detected in all high myopia cases but not in other family members without high myopia or the controls. The variant was predicted to be benign by online software programmes. However, modelling of the three-dimensional structure of the protein clearly revealed conformational changes caused by the mutation., Conclusions: A missense mutation in the KRT12 gene was identified in this Chinese family, which may be associated with the pathogenesis of high myopia., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Case Summary The patient is a 42-year-old female who presented with a de novo missense variant in the PRPS1 gene. Her phenotype includes asymmetric retinal dystrophy with sensory esotropia, congenital sensorineural hearing loss, neuropathy, and severe tremors with recent-onset ataxia. This contributes a new presentation of ophthalmic and neurological findings to the literature.

Purpose: The biallelic variant of MAB21L1 has previously been documented in conjunction with the autosomal recessive cerebellar, ocular, craniofacial, and genital syndrome (COFG). The purpose of this study was to investigate the gene-disease association of MAB21L1 and the newly discovered autosomal dominant (AD) microphthalmia., Methods: We report the presence of an exceptionally rare missense variant in a single allele of the Arg51 codon of MAB21L1 among four individuals from a single family diagnosed with microphthalmia, which suggesting an autosomal dominant inheritance pattern. Subsequently, based on comprehensive literature review, we identified another 13 families that have reported cases of autosomal dominant microphthalmos., Results: Genotype-phenotype analysis revealed that patients with a single allele missense variant in MAB21L1 exhibited solely eye abnormalities. This starkly diverged from the clinical presentation of COFG, typified by the concurrent occurrence of ocular and extraocular symptoms stemming from the biallelic variant in MAB21L1 . Our findings revealed that the heterozygous pathogenic variant in MAB21L1 resulted in the emergence of autosomal dominant microphthalmia. By combining these genetic and experimental evidence, the clinical validity of MAB21L1 and the emerging autosomal dominant microphthalmia can be regarded as moderate., Conclusion: In summary, there is sufficient convincing evidence to prove that MAB21L1 is a novel pathogenic gene responsible for autosomal dominant microphthalmia, thus offering valuable insights for precise diagnosis and targeted therapeutic interventions in cases of microphthalmia.

Marfanoid habitus and intellectual disability (MHID) co-occur in multiple neurodevelopmental disorders (NDD). Among those, Lujan-Fryns, an X-linked genetic disorder associated with variants in MED12 was the first such syndrome identified. Accurate molecular diagnosis for these MHID syndromes remains a challenge due to significant clinical and genetic heterogeneity. We present a case report of a 20-year-old male patient with MHID and severe social anxiety. A comprehensive clinical evaluation, including morphotype assessment, cognitive, and psychometric and genetic testing, was conducted to provide a detailed understanding of the patient's complex clinical presentation. Psychometric assessments revealed severe social anxiety and various cognitive and emotional challenges. Despite some autism-like symptoms, the patient's clinical presentation was more aligned with mild intellectual disability. Exome sequencing was inconclusive but identified a heterozygous de novo missense variant in the PCDHGA5 gene. This gene is not known in human pathology yet, but we also report a second patient with a syndromic neurodevelopmental disorder and a rare de novo variant which leads us to propose this as a candidate gene. Our findings emphasize the importance of multidisciplinary approach in the diagnosis and management of MHID. This case report underscores the need for objective clinical evaluations and standardized tools to better understand the complex clinical profiles of patients with NDDs. The identification of novel PCDHGA5 gene variants adds this gene's candidacy to the genetic landscape of MHID-NDD, warranting further investigation to determine its potential contribution., (© 2024 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)

Objective:  The clinical characteristics, genetic mutation spectrum, treatment strategies and prognoses of 15 children with Dent disease were retrospectively analyzed to improve pediatricians' awareness of and attention to this disease., Methods:  We analyzed the clinical and laboratory data of 15 Chinese children with Dent disease who were diagnosed and treated at our hospital between January 2017 and May 2023 and evaluated the expression of the CLCN5 and OCRL1 genes., Results:  All 15 patients were male and complained of proteinuria, and the incidence of low-molecular-weight proteinuria (LMWP) was 100.0% in both Dent disease 1 (DD1) and Dent disease 2 (DD2) patients. The incidence of hypercalciuria was 58.3% (7/12) and 66.7% (2/3) in DD1 and DD2 patients, respectively. Nephrocalcinosis and nephrolithiasis were found in 16.7% (2/12) and 8.3% (1/12) of DD1 patients, respectively. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS) in 1 patient, minimal change lesion in 5 patients, and small focal acute tubular injury in 1 patient. A total of 11 mutations in the CLCN5 gene were detected, including 3 missense mutations (25.0%, c.1756C > T, c.1166T > G, and c.1618G > A), 5 frameshift mutations (41.7%, c.407delT, c.1702&#95;c.1703insC, c.137delC, c.665&#95;666delGGinsC, and c.2200delG), and 3 nonsense mutations (25.0%, c.776G > A, c.1609C > T, and c.1152G > A). There was no significant difference in age or clinical phenotype among patients with different mutation types ( p  > 0.05). All three mutations in the OCRL1 gene were missense mutations (c.1477C > T, c.952C > T, and c.198A > G)., Conclusion:  Pediatric Dent disease is often misdiagnosed. Protein electrophoresis and genetic testing can help to provide an early and correct diagnosis.