Novel homozygous frameshift insertion variant in the last exon of the EDARADD causing hypohidrotic ectodermal dysplasia in two siblings: case report and review of the literature.

BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that results in the abnormal development of structures derived from ectodermal tissue. This rare condition predominantly affects the hair, nails, eccrine glands, and teeth. While HED can be caused by various genes, the EDA, EDAR, EDARADD, and WNT10A genes account for approximately 90% of cases. Notably, HED forms associated with variants in the EDA, EDAR, or EDARADD genes may exhibit similar phenotypes due to defects in a common signaling pathway. Proper interaction among the products of these genes is crucial for the activation of the nuclear factor (NF-κB) signaling pathway, which subsequently regulates the transcription of targeted genes. The EDARADD gene, in particular, harbors one of the rarest reported variants associated with HED. CASE PRESENTATION: Five-and two-years-old brothers born into consanguineous parents were examined at our outpatient medical genetics clinic at Sanliurfa Training and Research Hospital, Turkey. Both displayed the same classical phenotypic features of HED. The elder had a very sparse dark and brittle hair, sparse eyebrows and eyelashes, conical upper and lower premolar teeth with hypodontia, widely spaced teeth, very dry skin, mildly prominent forehead, and periorbital wrinkles. The younger one showed the same, but less severe, clinical features. After thorough examination and patient history evaluation, targeted next-generation sequencing analysis yielded the novel homozygous insertion variant c.322_323insCGGGC p.(Arg108ProfsTer7) in EDARADD. The mutation has not been reported to date in the literature. CONCLUSIONS: In this report, we present two siblings exhibiting classical HED symptoms and a novel insertion variant of the EDARADD gene, which leads to a frameshift introducing a stop codon. Both brothers inherited such mutation from their parents, who were heterozygous carriers of the same variant. The present study may shed light about the pathogenic mechanisms underlying HED, and expand the spectrum of EDARADD gene variants associated with this condition.

It is Time to Screen for Homozygous Familial Hypercholesterolemia in the United States.

Homozygous familial hypercholesterolemia (HoFH) is an ultra-rare inherited condition that affects approximately one in 300,000 people. The disorder is characterized by extremely high, life-threatening levels of low-density lipoprotein (LDL) cholesterol from birth, leading to significant premature cardiovascular morbidity and mortality, if left untreated. Homozygous familial hypercholesterolemia is severely underdiagnosed and undertreated in the United States (US), despite guidelines recommendations for universal pediatric lipid screening in children aged 9-11. Early diagnosis and adequate treatment are critical in averting premature cardiovascular disease in individuals affected by HoFH. Yet, an unacceptably high number of people living with HoFH remain undiagnosed, misdiagnosed, and/or receive a late diagnosis, often after a major cardiovascular event. The emergence of novel lipid-lowering therapies, along with the realization that diagnosis is too often delayed, have highlighted an urgency to implement policies that ensure timely detection of HoFH in the US. Evidence from around the world suggests that a combination of universal pediatric screening and cascade screening strategies constitutes an effective approach to identifying heterozygous familial hypercholesterolemia (HeFH). Nevertheless, HoFH and its complications manifest much earlier in life compared to HeFH. To date, little focus has been placed on the detection of HoFH in very young children and/or infants. The 2023 Updated European Atherosclerosis Society Consensus Statement on HoFH has recommended, for the first time, broadening pediatric guidelines to include lipid screening of newborn infants. Some unique aspects of HoFH need to be considered before implementing newborn screening. As such, insights from pilot studies conducted in Europe may provide some preliminary guidance. Our paper proposes a set of actionable measures that states can implement to reduce the burden of HoFH. It also outlines key research and policy gaps that need to be addressed in order to pave the way for universal newborn screening of HoFH in the US.

Evinacumab and Cardiovascular Outcome in Patients With Homozygous Familial Hypercholesterolemia.

BACKGROUND: Patients with homozygous familial hypercholesterolemia (HoFH) remain at very high cardiovascular risk despite the best standard of care lipid-lowering treatment. The addition of evinacumab, an angiopoietin-like protein 3 monoclonal antibody, more than halves low-density lipoprotein cholesterol in short-term studies. This study evaluated whether the evinacumab response was durable in the long term and improved cardiovascular outcome. METHODS: The OLE ELIPSE HoFH (Open-Label Extension to Evinacumab Lipid Studies in Patients With HoFH) study included newly diagnosed patients and those completing the ELIPSE HoFH trial, on stable lipid-lowering therapy including lipoprotein apheresis but not lomitapide. All patients received evinacumab (15 mg/kg intravenously) every 4 weeks, with no change in concomitant lipid-lowering treatment during the first 6 months. The primary efficacy end points were the mean absolute and percentage changes in low-density lipoprotein cholesterol from baseline to 6 months. A key secondary end point was cardiovascular event-free survival, which was compared with a control HoFH cohort not treated with evinacumab or lomitapide and matched for age, sex, and lipoprotein apheresis, derived from French Registry of Familial hypercholesterolemia. RESULTS: Twelve patients, 5 women and 7 men (12-57 years), were enrolled in 3 centers in France. At 6 months, the mean low-density lipoprotein cholesterol reduction with evinacumab was 3.7 mmol/L or 56% (from 6.5 mmol/L at baseline to 2.8 mmol/L; P<0.0001) and was sustained over the median 3.5-year follow-up. No patients on evinacumab experienced cardiovascular events versus 13 events for 5/21 (24%) over 4 years in the control cohort (likelihood P=0.0267). CONCLUSIONS: Real-life, long-term evinacumab adjunctive to lipid-lowering therapy including lipoprotein apheresis led to sustained low-density lipoprotein cholesterol lowering and improved cardiovascular event-free survival of patients with HoFH.

A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections.

RHOH, an atypical small GTPase predominantly expressed in hematopoietic cells, plays a vital role in immune function. A deficiency in RHOH has been linked to epidermodysplasia verruciformis, lung disease, Burkitt lymphoma and T cell defects. Here, we report a novel germline homozygous RHOH c.245G > A (p.Cys82Tyr) variant in a 21-year-old male suffering from recurrent, invasive, opportunistic infections affecting the lungs, eyes, and brain. His sister also succumbed to a lung infection during early adulthood. The patient exhibited a persistent decrease in CD4+ T, B, and NK cell counts, and hypoimmunoglobulinemia. The patient's T cell showed impaired activation upon in vitro TCR stimulation. In Jurkat T cells transduced with RHOHC82Y, a similar reduction in activation marker CD69 up-regulation was observed. Furthermore, the C82Y variant showed reduced RHOH protein expression and impaired interaction with the TCR signaling molecule ZAP70. Together, these data suggest that the newly identified autosomal-recessive RHOH variant is associated with T cell dysfunction and recurrent opportunistic infections, functioning as a hypomorph by disrupting ZAP70-mediated TCR signaling.

A novel homozygous missense variant identified in the myosin VIIA motor domain of a Moroccan patient with usher syndrome.

BACKGROUND: Usher syndrome 1 (USH1) is the most severe subtype of Usher syndrome characterized by severe sensorineural hearing impairment, retinitis pigmentosa, and vestibular areflexia. USH1 is usually induced by variants in MYO7A, a gene that encodes the myosin-VIIa protein. Myosin-VIIA is effectively involved in intracellular molecular traffic essential for the proper function of the cochlea, the retinal photoreceptors, and the retinal pigmented epithelial cells. METHODS AND RESULTS: In this study, we report a new homozygous missense variant (NM_000260.4: c.1657 C > T p.(His553Tyr)) in MYO7A of a 28-year-old female with symptoms consistent with USH1. This variant, c.1657 C > T p.(His553Tyr) is positioned in the highly conserved myosin-VIIA motor domain. Previous studies showed that variants in this domain might disrupt the ability of the protein to bind to actin and thus cause the disorder. CONCLUSIONS: Our findings contribute to our understanding of the phenotypic and mutational spectrum of USH1 associated with autosomal recessive MYO7A variants and emphasize the important role of molecular testing in accurately diagnosing this syndrome. More advanced research is required to understand the functional effect of the identified variant and the genotype-phonotype correlations of MYO7A-related Usher syndrome 1.

Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m6A site accessibility.

Hypomyelinating leukodystrophy (HLD) is an autosomal recessive disorder characterized by defective central nervous system myelination. Exome sequencing of two siblings with severe cognitive and motor impairment and progressive hypomyelination characteristic of HLD revealed homozygosity for a missense single-nucleotide variant (SNV) in EPRS1 (c.4444 C > A; p.Pro1482Thr), encoding glutamyl-prolyl-tRNA synthetase, consistent with HLD15. Patient lymphoblastoid cell lines express markedly reduced EPRS1 protein due to dual defects in nuclear export and cytoplasmic translation of variant EPRS1 mRNA. Variant mRNA exhibits reduced METTL3 methyltransferase-mediated writing of N6-methyladenosine (m6A) and reduced reading by YTHDC1 and YTHDF1/3 required for efficient mRNA nuclear export and translation, respectively. In contrast to current models, the variant does not alter the sequence of m6A target sites, but instead reduces their accessibility for modification. The defect was rescued by antisense morpholinos predicted to expose m6A sites on target EPRS1 mRNA, or by m6A modification of the mRNA by METTL3-dCas13b, a targeted RNA methylation editor. Our bioinformatic analysis predicts widespread occurrence of SNVs associated with human health and disease that similarly alter accessibility of distal mRNA m6A sites. These results reveal a new RNA-dependent etiologic mechanism by which SNVs can influence gene expression and disease, consequently generating opportunities for personalized, RNA-based therapeutics targeting these disorders.

Genetic evaluation in indeterminate acute liver failure: A post hoc analysis.

BACKGROUND AND STUDY AIMS: There are limited data regarding indeterminate acute liver failure (ALF). The study aims to perform a post hoc analysis using genetic methods for the ALF cases with indeterminate etiology. PATIENTS AND METHODS: Stored blood samples from these patients with indeterminate ALF were collected. Whole-exome sequencing (WES) was used to evaluate the pathogenesis of indeterminate ALF. RESULTS: A total of 16 samples from 11 adult patients and 5 pediatric patients with indeterminate ALF were available. Among the adult patients, one female patient was identified with two heterozygous variants (c.2333G > T (p.Arg778Leu) and c.2310C > G (p.Leu770 = )) in the adenosine triphosphatase copper-transporting beta (ATP7B) gene, and two male patients were found to harbor heterozygous and homozygous variants (c.686C > A (p.Pro229Gln) plus homozygousvariantA(TA)6TAAinsTA (-), andc.1456 T > G (p.Tyr486Asp) plus c.211G > A (p.Gly71Arg)) in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene. For the pediatric patients, single heterozygous variant (c.2890C > T (p.Arg964Cys)) in the polymerase gamma (POLG) gene was found in 1 male child, and two heterozygous variants (c.1909A > G (p.Lys637Glu) and c.3646G > A (p.Val1216Ile)) in the tetratricopeptide repeat domain 37 (TTC37) gene were found in 1 female child. No variants clinically associated with known liver diseases were revealed in the remaining patients. CONCLUSION: These results expand the knowledge of ALF with indeterminate etiology. WES is helpful to reveal possible candidate genes for indeterminate ALF, but incomplete consistency between the genotype and phenotype in some cases still challenge the accurate diagnosis.

Radiosensitivity in a newborn with microcephalia: A case report of Nijmegen breakage syndrome.

AIM: Nijmegen breakage syndrome (NBS) is an autosomal recessive DNA repair disorder which is characterized by immunodeficiency and increased risk of lymphoproliferative malignancy. CASE: We observed an increase in the rate of chromosomal rearrangements in the cultured cells following an incidental radiograph for craniosynostosis in a newborn who was followed up due to microcephaly. We identified a homozygous deletion of c.657_661delACAAA/p.Lys219fs (rs587776650) in the NBN gene through whole exome sequencing. CONCLUSION: It is crucial to thoroughly examine the clinical features of newborns with microcephaly and consider chromosomal instability syndromes just like Nijmegen breakage syndrome. Not overlooking radiosensitivity, which is a characteristic feature of this syndrome, is a vital condition to the patient's survival time.

Revealing a New Homozygous Variant in CYP17A1 c.908G>A (p. Gly303Asp) by Genotyping a Chinese Patient with 46, XY 17a-Hydroxylase/17,20-Lyase Deficiency and Adrenal Space-Occupying Lesion.

BACKGROUND: 17α-hydroxylase/17,20-lyase deficiency (17OHD) is an autosomal recessive genetic disorder caused by a mutation of the cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1). This study reports the case of a 22-year-old Chinese patient (46, XY) with 17OHD and a unilateral adrenal space-occupying lesion. METHODS: The patient underwent serological, radiographic, genetic, and molecular analyses including whole-genome exome sequencing through high-throughput sequencing (HTS) technology to analyze the genetic conditions of both the patient and her parents. Additionally, chromosomal karyotype analysis was performed. The impact of the novel mutation on protein conformation was investigated by examining the three-dimensional structure of human CYP17A1 using the SWISS-MODEL website tool (PDB code 3RUK). RESULTS: The patient had a chromosomal karyotype 46, XY, and presented with hypertension, hypokalemia, and male pseudohermaphroditism. Furthermore, decreased levels of testosterone, dehydroepiandrosterone sulfate, and estradiol, along with increased levels of progesterone, luteinizing hormone, and follicle-stimulating hormone (FSH), were observed. DNA sequencing revealed a homozygous mutation (c.908G>A, p.G303A) in the fifth exon of the CYP17A1. Both parents carried a heterozygous c.908G>A mutation in the same exon, confirming the inheritance of the patient's exonic mutation. CONCLUSION: For the first time, this study reports a novel homozygous mutation (c.908G>A in the fifth exon) in CYP17A1. Modeling analysis of CYP17A1 suggested that the substitution of glycine with aspartic acid at position 303 induces alterations in the number, structure, and electrostatic potential of the protein's local binding sites. The p.G303A mutation may possess pathogenic properties. Our study expands the mutation spectrum of CYP17A1.

A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts.

BACKGROUND: This report presents a clinical case of syndromic rod-cone dystrophy due to a splice site variant in the ARL2BP gene causing situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts. The presence of renal agenesis and cryptorchidism expands the clinical manifestations due to ARL2BP variants. The detailed, long-term follow-up contributes valuable insights into disease progression, aiding clinical diagnosis and patient management. CASE PRESENTATION: The male patient complained of photophobia as the first symptom when he was 20 years old followed by nyctalopia, loss of central visual acuity and peripheral visual field ten years later. Genetic analysis identified a likely pathogenic homozygous variant (c.294-1G > C) involving the splicing acceptor site of intron 4. Reported symptoms together with full-field stimulus threshold testing, electroretinogram and advanced multimodal imaging allowed us to recognize the typical characteristics of a mixed retinal dystrophy. Despite the end-stage retinal disease, this patient still retained a useful residual vision at 63 years and had a slow disease progression during the last 5 years of evaluation. DISCUSSION AND CONCLUSIONS: Our findings underscore the variable clinical presentation of ARL2BP variants, emphasizing the importance of a nuanced approach in diagnosing and managing patients. The presence of renal cysts warrants consideration of a differential diagnosis, particularly with Senior-Loken (SLS), Bardet-Biedl (BBS) and Joubert syndromes (JS) but also with Short Rib Thoracic Dysplasia 9, highlighting the need for careful phenotypic evaluation in these cases.

Impact of genotype on multi-organ iron and complications in patients with non-transfusion-dependent ß-thalassemia intermedia.

We evaluated the impact of the genotype on clinical and hematochemical features, hepatic and cardiac iron levels, and endocrine, hepatic, and cardiovascular complications in non-transfusion-dependent (NTD) ß-thalassemia intermedia (TI) patients. Sixty patients (39.09 ± 11.11 years, 29 females) consecutively enrolled in the Myocardial Iron Overload in Thalassemia project underwent Magnetic Resonance Imaging to quantify iron overload, biventricular function parameters, and atrial areas and to detect replacement myocardial fibrosis. Three groups of patients were identified: homozygous ß+ (N = 18), heterozygous ß0ß+ (N = 22), and homozygous ß0 (N = 20). The groups were homogeneous for sex, age, splenectomy, hematochemical parameters, chelation therapy, and iron levels. The homozygous ß° genotype was associated with significantly higher biventricular end-diastolic and end-systolic volume indexes and bi-atrial area indexes. No difference was detected in biventricular ejection fractions or myocardial fibrosis. Extramedullary hematopoiesis and leg ulcers were significantly more frequent in the homozygous ß° group compared to the homozygous ß+ group. No association was detected between genotype and liver cirrhosis, hypogonadism, hypothyroidism, osteoporosis, heart failure, arrhythmias, and pulmonary hypertension. Heart remodelling related to a high cardiac output state cardiomyopathy, extramedullary hematopoiesis, and leg ulcers were more pronounced in patients with the homozygous ß° genotype compared to the other genotypes analyzed. The knowledge of the genotype can assist in the clinical management of NTD ß-TI patients.

Clinical practice recommendations on lipoprotein apheresis for children with homozygous familial hypercholesterolaemia: An expert consensus statement from ERKNet and ESPN.

Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is used for decades, lowering serum LDL-C levels by more than 70% directly after the treatment. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.

[Methylthioadenosine phosphorylase and p16 as surrogate diagnostic markers for CDKN2A homozygous deletion in brain tumors].

Objective: To examine whether immunohistochemistry of methylthioadenosine phosphorylase (MTAP) and p16 could be used to predict the CDKN2A status in various brain tumors. Methods: A total of 118 cases of IDH-mutant astrocytomas, 16 IDH-wildtype glioblastoma, 17 polymorphic xanthoastrocytoma (PXA) and 20 meningiomas diagnosed at Xuanwu Hospital, Capital Medical University, Beijing, China from November 2017 to October 2023 were collected and analyzed. The CDKN2A status was detected by using fluorescence in situ hybridization or next-generation sequencing. Expression of MTAP and p16 proteins was detected with immunohistochemistry. The association of loss of MTAP/p16 expression with CDKN2A homozygous/heterozygous deletion was examined. Results: Among the 118 cases of IDH-mutant astrocytoma, 13 cases showed homozygous deletion of CDKN2A. All of them had no expression of MTAP while 9 cases had no expression of p16. Among the 16 cases of IDH wild-type glioblastoma, 6 cases showed homozygous deletion of CDKN2A. All 6 cases had no expression of MTAP, while 3 of these cases had no expression of p16 expression. Among the 17 PXA cases, 4 cases showed homozygous deletion of CDKN2A, and the expression of MTAP and p16 was also absent in these 4 cases. Among the 20 cases of meningiomas, 4 cases showed homozygous deletion of CDKN2A. Their expression of MTAP and p16 was also absent. Among the four types of brain tumors, MTAP was significantly correlated with CDKN2A homozygous deletion (P<0.05), with a sensitivity of 100%. However, it was only significantly correlated with the loss of heterozygosity (LOH) of CDKN2A in astrocytomas (P<0.001). P16 was associated with CDKN2A homozygous deletion in IDH-mutant astrocytoma and PXA (P<0.001), but not with the LOH of CDKN2A. Its sensitivity and specificity were lower than that of MTAP. Conclusions: MTAP could serve as a predictive surrogate for CDKN2A homozygous deletion in adult IDH-mutant astrocytoma, PXA, adult IDH-wildtype glioblastoma and meningioma. However, p16 could only be used in the first two tumor types, and its specificity and sensitivity are lower than that of MTAP.

A naturally occurring canine model of syndromic congenital microphthalmia.

In humans, the prevalence of congenital microphthalmia is estimated to be 0.2-3.0 for every 10,000 individuals, with nonocular involvement reported in ∼80% of cases. Inherited eye diseases have been widely and descriptively characterized in dogs, and canine models of ocular diseases have played an essential role in unraveling the pathophysiology and development of new therapies. A naturally occurring canine model of a syndromic disorder characterized by microphthalmia was discovered in the Portuguese water dog. As nonocular findings included tooth enamel malformations, stunted growth, anemia, and thrombocytopenia, we hence termed this disorder Canine Congenital Microphthalmos with Hematopoietic Defects. Genome-wide association study and homozygosity mapping detected a 2 Mb candidate region on canine chromosome 4. Whole-genome sequencing and mapping against the Canfam4 reference revealed a Short interspersed element insertion in exon 2 of the DNAJC1 gene (g.74,274,883ins[T70]TGCTGCTTGGATT). Subsequent real-time PCR-based mass genotyping of a larger Portuguese water dog population found that the homozygous mutant genotype was perfectly associated with the Canine Congenital Microphthalmos with Hematopoietic Defects phenotype. Biallelic variants in DNAJC21 are mostly found to be associated with bone marrow failure syndrome type 3, with a phenotype that has a certain degree of overlap with Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and reports of individuals showing thrombocytopenia, microdontia, and microphthalmia. We, therefore, propose Canine Congenital Microphthalmos with Hematopoietic Defects as a naturally occurring model for DNAJC21-associated syndromes.

USP8-governed GPX4 homeostasis orchestrates ferroptosis and cancer immunotherapy.

Ferroptosis is an iron-dependent type of regulated cell death resulting from extensive lipid peroxidation and plays a critical role in various physiological and pathological processes. However, the regulatory mechanisms for ferroptosis sensitivity remain incompletely understood. Here, we report that homozygous deletion of Usp8 (ubiquitin-specific protease 8) in intestinal epithelial cells (IECs) leads to architectural changes in the colonic epithelium and shortens mouse lifespan accompanied by increased IEC death and signs of lipid peroxidation. However, mice with heterozygous deletion of Usp8 in IECs display normal phenotype and become resistant to azoxymethane/dextran sodium sulfate-induced colorectal tumorigenesis. Mechanistically, USP8 interacts with and deubiquitinates glutathione peroxidase 4 (GPX4), leading to GPX4 stabilization. Thus, USP8 inhibition destabilizes GPX4 and sensitizes cancer cells to ferroptosis in vitro. Notably, USP8 inhibition in combination with ferroptosis inducers retards tumor growth and enhances CD8+ T cell infiltration, which potentiates tumor response to anti-PD-1 immunotherapy in vivo. These findings uncover that USP8 counteracts ferroptosis by stabilizing GPX4 and highlight targeting USP8 as a potential therapeutic strategy to boost ferroptosis for enhancing cancer immunotherapy.

Splice modulators target PMS1 to reduce somatic expansion of the Huntington's disease-associated CAG repeat.

Huntington's disease (HD) is a dominant neurological disorder caused by an expanded HTT exon 1 CAG repeat that lengthens huntingtin's polyglutamine tract. Lowering mutant huntingtin has been proposed for treating HD, but genetic modifiers implicate somatic CAG repeat expansion as the driver of onset. We find that branaplam and risdiplam, small molecule splice modulators that lower huntingtin by promoting HTT pseudoexon inclusion, also decrease expansion of an unstable HTT exon 1 CAG repeat in an engineered cell model. Targeted CRISPR-Cas9 editing shows this effect is not due to huntingtin lowering, pointing instead to pseudoexon inclusion in PMS1. Homozygous but not heterozygous inactivation of PMS1 also reduces CAG repeat expansion, supporting PMS1 as a genetic modifier of HD and a potential target for therapeutic intervention. Although splice modulation provides one strategy, genome-wide transcriptomics also emphasize consideration of cell-type specific effects and polymorphic variation at both target and off-target sites.

Exploring genomic inbreeding and selection signatures in a commercial Brangus herd through functional annotation.

Composite breeds, including Brangus, are widely utilized in subtropical and tropical regions to harness the advantages of both Bos t. taurus and Bos t. indicus breeds. The formation and subsequent selection of composite breeds may result in discernible signatures of selection and shifts in genomic population structure. The objectives of this study were to 1) assess genomic inbreeding, 2) identify signatures of selection, 3) assign functional roles to these signatures in a commercial Brangus herd, and 4) contrast signatures of selection between selected and non-selected cattle from the same year. A total of 4035 commercial Brangus cattle were genotyped using the GGP-F250K array. Runs of Homozygosity (ROH) were used to identify signatures of selection and calculate genomic inbreeding. Quantitative trait loci (QTL) enrichment analysis and literature search identified phenotypic traits linked to ROH islands. Genomic inbreeding averaged 5%, primarily stemming from ancestors five or more generations back. A total of nine ROH islands were identified, QTL enrichment analysis revealed traits related to growth, milk composition, carcass, reproductive, and meat quality traits. Notably, the ROH island on BTA14 encompasses the pleiomorphic adenoma (PLAG1) gene, which has been linked to growth, carcass, and reproductive traits. Moreover, ROH islands associated with milk yield and composition were more pronounced in selected replacement heifers of the population, underscoring the importance of milk traits in cow-calf production. In summary, our research sheds light on the changing genetic landscape of the Brangus breed due to selection pressures and reveals key genomic regions impacting production traits.

Accelerated MEN2A in homozygous RET carriers in the context of consanguinity.

BACKGROUND: Homozygous mutations, 2 identical gene versions (alleles), 1 from each biological parent, are exceptional. Clinical descriptions of affected families, comprising few carriers only, are scattered throughout the literature, hindering evidence generation. METHODS: Included in this literature analysis were 5 RET families with ≥1 homozygous carrier and ≥3 heterozygous carriers per family. RESULTS: In consanguineous families with first-degree cousins, homozygotes presented with node-positive medullary thyroid cancer and pheochromocytoma in their mid-teens, whereas heterozygotes presented in their end-30s and early 40s. Homozygotes developed node-positive medullary thyroid cancer 27.4 years and pheochromocytoma 23 years earlier than heterozygotes. These age differences were smaller in the 15 families carrying founder mutation p.Leu666delinsAsnSer, whereas homozygotes developed node-positive medullary thyroid cancer in their mid-40s, 6 years earlier than heterozygotes in their early 50s. CONCLUSION: These results, limited in scope and size and modulated by extent of consanguinity, are consistent with moderate dose-response effects accelerating MEN2A development.

Novel homozygous ADK out-of-frame deletion causes adenosine kinase deficiency with rare phenotypes of sepsis, metabolites disruption and neutrophil dysfunction.

Adenosine kinase deficiency (OMIM #614300) is a type of inborn errors of metabolism with multiorgan symptoms primarily neurological disorders, hepatic impairment, global developmental delay, and mild dysmorphism. The genetic causes of adenosine kinase deficiency are homozygous or compound heterozygous loss-of-function variants of ADK. To date, fewer than 25 cases of adenosine kinase deficiency have been reported worldwide and none have been reported in China. In this research, trio whole-exome sequencing (Trio-WES) identified a novel homozygous ADK (NM_001123.4) out-of-frame deletion, c.518_519delCA (p.Thr173Serfs*15), in a Chinese patient with rare phenotypes of sepsis, metabolites disruption and neutrophil dysfunction. This variant was dysfunctional, with marked reduction of ADK level in both the patient's peripheral blood and cells transfected with the corresponding variant. Additionally, metabolomics detected by high-throughput mass spectrometry showed disturbances in the methionine (Met) and energy pathway. RNA sequencing (RNA-seq) of the patient's peripheral blood suggested a defective anti-inflammatory response characterized by impaired neutrophil activation, migration, and degranulation, which might be the primary cause for the sepsis. To our knowledge, we identified the first Chinese patient of adenosine kinase deficiency with a novel homozygous out-of-frame deletion in ADK causing multiorgan disorders, metabolites disruption, rare phenotypes of sepsis, and neutrophil dysfunction. Our findings broaden the genetic spectrum and pathogenic mechanisms of adenosine kinase deficiency.