Genetic Causes Research Articles

Mechanisms and pathologies of human mitochondrial DNA replication and deletion formation.

Human mitochondria possess a multi-copy circular genome, mitochondrial DNA (mtDNA), that is essential for cellular energy metabolism. The number of copies of mtDNA per cell, and their integrity, are maintained by nuclear-encoded mtDNA replication and repair machineries. Aberrant mtDNA replication and mtDNA breakage are believed to cause deletions within mtDNA. The genomic location and breakpoint sequences of these deletions show similar patterns across various inherited and acquired diseases, and are also observed during normal ageing, suggesting a common mechanism of deletion formation. However, an ongoing debate over the mechanism by which mtDNA replicates has made it difficult to develop clear and testable models for how mtDNA rearrangements arise and propagate at a molecular and cellular level. These deletions may impair energy metabolism if present in a high proportion of the mtDNA copies within the cell, and can be seen in primary mitochondrial diseases, either in sporadic cases or caused by autosomal variants in nuclear-encoded mtDNA maintenance genes. These mitochondrial diseases have diverse genetic causes and multiple modes of inheritance, and show notoriously broad clinical heterogeneity with complex tissue specificities, which further makes establishing genotype-phenotype relationships challenging. In this review, we aim to cover our current understanding of how the human mitochondrial genome is replicated, the mechanisms by which mtDNA replication and repair can lead to mtDNA instability in the form of large-scale rearrangements, how rearranged mtDNAs subsequently accumulate within cells, and the pathological consequences when this occurs.

Meeting Report for the 2023 International Scientific Conference on Complex Lymphatic Anomalies

Objectives: Complex lymphatic anomalies (CLAs) are rare diseases with variable clinical manifestations caused by the abnormal development of lymphatic vessels. The Lymphatic Malformation Institute (LMI), Lymphangiomatosis & Gorham’s Disease Alliance (LGDA), and LGD Alliance Europe sponsored an international conference on CLAs so leaders in the field could discuss recent advances in research on CLAs. Methods: The conference occurred in Dallas, Texas, between September 29th and September 30th, 2023. The event had 22 distinguished speakers and 38 attendees. Additional researchers, clinicians, and patients attended the conference virtually. Results: In this article, we summarize the key takeaways from the meeting. The conference emphasized the crucial role of the patient voice in guiding research, and attendees heard stories from patients and parents of children with CLAs. The conference covered topics such as the genetic causes of CLAs, preclinical models, clinical advances, new technologies for CLA research, lymphatic imaging, and patient-centered research. Videos of all the presentations can be found on the LGDA website. Conclusions: The meeting revealed that while progress has been made, many challenges still exist surrounding the diagnosis and treatment of CLAs. Sustained research efforts are necessary to fill the gaps in knowledge and improve the care and quality of life of CLA patients.

FANCM Gene Variants in a Male Diagnosed with Sertoli Cell-Only Syndrome and Diffuse Astrocytoma

Azoospermia is a form of male infertility characterized by a complete lack of spermatozoa in the ejaculate. Sertoli cell-only syndrome (SCOS) is the most severe form of azoospermia, where no germ cells are found in the tubules. Recently, FANCM gene variants were reported as novel genetic causes of spermatogenic failure. At the same time, FANCM variants are known to be associated with cancer predisposition. We performed whole-exome sequencing on a male patient diagnosed with SCOS and a healthy father. Two compound heterozygous missense mutations in the FANCM gene were found in the patient, both being inherited from his parents. After the infertility assessment, the patient was diagnosed with diffuse astrocytoma. Immunohistochemical analyses in the testicular and tumor tissues of the patient and adequate controls showed, for the first time, not only the existence of a cytoplasmic and not nuclear pattern of FANCM in astrocytoma but also in non-mitotic neurons. In the testicular tissue of the SCOS patient, cytoplasmic anti-FANCM staining intensity appeared lower than in the control. Our case report raises a novel possibility that the infertile carriers of FANCM gene missense variants could also be prone to cancer development.

Characteristics, aetiology and implications for management of multiple primary renal tumours: a systematic review.

In a subset of patients with renal tumours, multiple primary lesions may occur. Predisposition to multiple primary renal tumours (MPRT) is a well-recognised feature of some inherited renal cancer syndromes. The diagnosis of MPRT should therefore provoke a thorough assessment for clinical and genetic evidence of disorders associated with predisposition to renal tumourigenesis. To better define the clinical and genetic characteristics of MPRT, a systematic literature review was performed for publications up to 3 April 2024. A total of 7689 patients from 467 articles were identified with MPRT. Compared to all patients with renal cell carcinoma (RCC), patients with MPRT were more likely to be male (71.8% versus 63%) and have an earlier age at diagnosis (<46 years, 32.4% versus 19%). In 61.1% of cases MPRT were synchronous. The proportion of cases with similar histology and the proportion of cases with multiple papillary renal cell carcinoma (RCC) (16.1%) were higher than expected. In total, 14.9% of patients with MPRT had a family history of cancer or were diagnosed with a hereditary RCC associated syndrome with von Hippel-Lindau (VHL) disease being the most common one (69.7%), followed by Birt-Hogg-Dubé (BHD) syndrome (14.2%). Individuals with a known or likely genetic cause were, on average, younger (43.9 years versus 57.1 years). In rare cases intrarenal metastatic RCC can phenocopy MPRT. We review potential genetic causes of MPRT and their implications for management, suggest an approach to genetic testing for individuals presenting with MPRT and considerations in cases in which routine germline genetic testing does not provide a diagnosis.

Structure-based network analysis predicts pathogenic variants in human proteins associated with inherited retinal disease.

Advances in gene sequencing technologies have accelerated the identification of genetic variants, but better tools are needed to understand which are causal of disease. This would be particularly useful in fields where gene therapy is a potential therapeutic modality for a disease-causing variant such as inherited retinal disease (IRD). Here, we apply structure-based network analysis (SBNA), which has been successfully utilized to identify variant-constrained amino acid residues in viral proteins, to identify residues that may cause IRD if subject to missense mutation. SBNA is based entirely on structural first principles and is not fit to specific outcome data, which makes it distinct from other contemporary missense prediction tools. In 4 well-studied human disease-associated proteins (BRCA1, HRAS, PTEN, and ERK2) with high-quality structural data, we find that SBNA scores correlate strongly with deep mutagenesis data. When applied to 47 IRD genes with available high-quality crystal structure data, SBNA scores reliably identified disease-causing variants according to phenotype definitions from the ClinVar database. Finally, we applied this approach to 63 patients at Massachusetts Eye and Ear (MEE) with IRD but for whom no genetic cause had been identified. Untrained models built using SBNA scores and BLOSUM62 scores for IRD-associated genes successfully predicted the pathogenicity of novel variants (AUC = 0.851), allowing us to identify likely causative disease variants in 40 IRD patients. Model performance was further augmented by incorporating orthogonal data from EVE scores (AUC = 0.927), which are based on evolutionary multiple sequence alignments. In conclusion, SBNA can used to successfully identify variants as causal of disease in human proteins and may help predict variants causative of IRD in an unbiased fashion.

Myoclonus: an update.

Myoclonus, a common hyperkinetic movement disorder, can be disabling for patients. It is important to identify and classify myoclonus correctly to ensure appropriate workup and treatment. While the clinical history, examination, and process of classifying myoclonus remain largely unchanged, new causes and triggers for myoclonus are being elucidated, and new genetic causes have been found. Treatment can be challenging, though preliminary data about new options has been promising. In this article, we will briefly outline the process of classifying and treating myoclonus. We will then discuss three specific scenarios where myoclonus has been identified: myoclonus associated with SARS-CoV-2 infections, spinal myoclonus following surgery or anesthesia of the spine, and auricular myoclonus. We will also discuss new genetic findings associated with myoclonus-dystonia, and promising results regarding the use of perampanel in treating myoclonus. The process of describing unique scenarios associated with myoclonus has helped us build our understanding of the causes, genetic background, expected prognosis, and effective treatment of specific types of myoclonus. We hope that further studies on this topic will help tailor treatment.

RESCUED (REgistry for Sudden Cardiac and UnExpected Death): the German registry for families affected by sudden cardiac death in the young

Abstract Background Sudden cardiac death in the young (SCDY) refers to an abrupt and unexpected cardiac arrest at a young age due to an underlying cardiac cause. Previous studies have shown that estimated more than 10% of SCDY victims 1 to 35 years of age suffered from a – previously often undiagnosed – rare genetic cardiac disorder. Due to the inheritability of such sequence variations in disease-causing cardiac genes, blood relatives of the deceased may equally be carriers of the causative genetic variation and therefore have an increased risk for cardiac arrhythmia. Purpose Despite sudden cardiac death (SCD) increasingly gaining global awareness, systematic data collection in form of registries is sparse. The data sets collected in the RESCUED registry allow for the identification of leading causes of SCDY in Germany and offer unique opportunities for further scientific analyses with the aim of revealing unrecognized trends, risk factors and clinical warning signs of SCDY. Methods Our workflows are based on international guidelines for post mortem examination of SCDY victims and clinical assessment of their relatives. Post-mortem assessment of the index patient includes autopsy, histology, toxicology, genetic testing and review of pre-mortem clinical data. Biological relatives within the family of the index patient undergo a cardiogenetic consultation, a set of cardiological examinations and a cascade genetic screening to determine each individual´s cardiac risk profile. Data is recorded in the registry through the web-based interface of the OSSE registry software (Open Source Registry System for Rare Diseases). Results Based on our experience with complex cases of SCD (over 150 SCDY cases and more than 450 relatives) and an in-depth literature research regarding SCD registries, we have developed designated questionnaires for systematic data collection for the deceased index patient and their biological relatives, respectively. We will present insights from the design of this registry, which represents a novel, pedigree-based approach to SCDY as a consequence of a possible underlying genetic cause, and offers a new viewing angle of identifying a possible cause of SCDY. For illustrational purposes, two SCDY cases including clinical data of the family members will be shown. Conclusions RESCUED is Germany´s first registry with a holistic, pedigree-based approach to SCDY. Apart from thoroughly documenting the cardiac deaths of young individuals under the age of 50, the phenotypes of their relatives are equally recorded. Ultimately, insights gained from the RESCUED registry will lead to improved and targeted diagnostic possibilities, risk stratification and, if need be, therapy in susceptible individuals, working towards the prevention of tragic deaths in affected families. The registry will also give insights into possible preceding warning signs and symptoms of SCDY regardless of whether the underlying cause is a rare genetic disease or not.

PKP2 gene therapy reduces ventricular arrhythmias, reverses ventricular remodeling, improves heart function, and reduces mortality in a mouse model of arrhythmogenic right ventricular cardiomyopathy

Abstract Introduction Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause of this disease, representing a significant unmet need. Purpose Mutations in desmosome gene Plakophilin-2 (PKP2) account for approximately 40% of ARVC cases and result in reduced gene expression. Our goal is to examine the feasibility and the efficacy of restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2. Methods Adeno-associated virus 9 (AAV9) was used to deliver a wild-type copy of PKP2 gene that is driven by a cardiac-selective promoter and expressed selectively in cardiomyocytes. Results We demonstrated that a single-dose AAV9-mediated PKP2 gene therapy effectively prevented disease onset before overt cardiomyopathy and attenuated disease progression after overt cardiomyopathy. Restoration of PKP2 expression led to a significant extension of lifespan by restoring cellular structures of desmosomes and gap junctions, preventing or halting decline in left ventricular ejection fraction, preventing or reversing dilation of the right ventricle, attenuating ventricular arrhythmia event frequency and severity, and preventing adverse fibrotic remodeling. Additional RNA sequencing analyses showed that durable restoration of PKP2 expression led to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology. Conclusion These results indicate that a cardiac-selective AAV9-mediated PKP2 gene therapy may be a promising one-time treatment for ARVC patients with PKP2 mutations.

Epilepsies with onset during the first year of life: A prospective study on syndromes, etiologies, and outcomes.

Infantile seizures cause great concern for both doctors and parents. In addition to modern neuroimaging and genetics, clinical tools helpful in predicting the course of the disease are needed. We prospectively studied the incidence, electroclinical characteristics and etiologies of epilepsy syndromes with onset before the age of 12 months and looked for prognostic determinants of outcome by age 24 months. From February 2017 through May 2019, we recruited all eligible infants diagnosed with epilepsy at our unit. Data on electroclinical studies, genetic investigations and drug response were gathered prospectively. The infants were given a structured neurological examination (Hammersmith Infantile Neurological examination [HINE] and Griffiths scales) at predetermined intervals until age 24 months at which age neurocognitive evaluation with Bayley scales was performed. Included were 60 infants (27 female). The mean onset age of epilepsy was 5.3 (±2.5 standard deviation) months. The incidence of epilepsy in the population-based cohort was 131 (95% confidence interval 99-172)/100 000. Epilepsy syndrome was identified in 80% and etiology in 58% of infants. Self-limited infantile epilepsy was the second most common syndrome (incidence 18/100 000) after infantile epileptic spasms syndrome. PRRT2 was the most common monogenic cause. At age 24 months, 37% of the infants had drug-resistant epilepsy (DRE) and half had a global developmental delay (GDD). Abnormal first HINE was the strongest predictor of GDD, followed by DRE and identified etiology. DRE was associated with structural etiology and GDD. Those with normal first HINE and good response to treatment had favorable outcomes, irrespective of the identified etiology. Our results support a high incidence of self-limited epilepsy in infancy and PRRT2 as the genetic cause in the first year of life. Notwithstanding the advances in etiological discovery, we want to highlight the importance of clinical evaluation as standardized neurological examination with HINE proved a valuable tool in prognostication. One in every 700-800 babies develop epilepsy within the first year after birth. Our study identified an epilepsy syndrome in 80% and the cause of epilepsy in 60% of the participants. By age 2 years, over one-third of the children still experienced seizures, and almost half faced significant developmental delay. Structural brain abnormalities increased the likelihood of difficult epilepsy and developmental challenges. Babies whose epilepsy was caused by a gene defect varied widely in development and response to medications. Babies with normal neurological examination at first visit, especially if their seizures stopped quickly, had favorable development.

P.094 Incidence of pathologically confirmed primary malignant brain tumours in Newfoundland and Labrador: an eight-year review spanning 2015-2022

Background: Considering regional and temporal trends, we sought to explore the incidence of primary malignant brain tumours in Newfoundland and Labrador. Methods: We reviewed all primary, malignant brain tumour cases from 2015-2022 confirmed by St. John’s Health Sciences Centre pathology reports. Incidence rates were standardized using the 2011 Canadian standard population. Results: We included 362 cases. The average annual age-standardized incidence rate of primary, malignant brain tumours per 100,000 was 7.0 (95% CI: 6.3-7.7), lower than the national average (7.93; 95% CI: 7.78-8.08). The incidence of glioblastoma (5.1; 95% CI: 4.5-5.7) was significantly higher than the national average (4.05; 95% CI: 3.95-4.16). Temporal trends revealed that oligodendroglioma incidence spiked from 0.5 (95% CI: 0.2-0.7) in 2015-2019 to 1.5 (95% CI: 0.4-2.6) in 2020 before returning to baseline in 2022. Regional trends indicated a lower incidence of malignant tumours in Labrador-Grenfell (5.1; 95% CI: 2.5-7.6), compared to 6.9 (95% CI: 6.2-7.6) averaged elsewhere. Conclusions: Higher rates of glioblastoma in Newfoundland and Labrador could have a genetic or multi-factorial cause. The increased occurrence of oligodendroglioma during the COVID-19 pandemic necessitates broader investigation, potentially linked to delays in patient care during this period. Regional trends could suggest less access to care in rural populations and underestimated incidence.

#2259 Preimplantation genetic testing in inherited kidney diseases

Abstract Background and Aims Identifying the underlying genetic cause in individuals with monogenic kidney disease allow counselling to provide prognosis and therapeutic options. In addition, discussions may extend to assessing the risk of having affected children and exploring family planning alternatives. Pre-conception counselling covers a wide range of considerations, including the expected pregnancy outcome for both mother and child, the risk of recurrence, invasive prenatal diagnosis, and the option of pre-implantation genetic testing (PGT). In this study we provide a clinical overview of PGT for monogenic kidney disease in our centre. Methods This is a retrospective cohort study of individuals with monogenic kidney disease counselled on our fertility clinic for PGT, in the Fundació Puigvert—Hospital de Sant Pau, Barcelona-Spain from January 2016 to 2023. Results During the study period, 751 visits were made to the fertility clinic, of which 8.3% (63/751) had a monogenic inherited kidney disease (IKD). Regarding the baseline characteristics of individuals with monogenic conditions, most were females (70%; 44/63). The mean age of the women was 33 years, most had no history of pregnancy prior to the first visit (73%). The mean anti-Mullerian hormone (AMH) level was 2.67 ng/ml, with 22% having levels below 1.1 ng/ml. Most cases (84%; 53/63) showed an autosomal dominant pattern of inheritance, with autosomal dominant polycystic kidney disease (ADPKD) being the primary cause in 66% of cases (42/63), followed by tuberous sclerosis complex in 8% (5/63). Autosomal recessive and X-linked disorders were each present in 8% (5/63). Table 1 shows the complete list of genetic kidney disease cases that consulted the fertility clinic. In terms of renal function, affected women had a mean renal function measured by estimated glomerular filtration rate (eGFR) of 90 mil/min/1.73 m2, with 74% having chronic kidney disease (CKD) category G1. Affected male had mean eGFR of 65 mL/min/1.73 m2, with only 38% (6/19 patients) having CKD-G1. Two (13%; 2/19) of the affected men had received a kidney transplant. Of the 63 couples who were counseled, 51% (32/63) agreed to proceed with PGT; 81% (26/32) underwent at least one cycle of ovarian stimulation, in vitro fertilization, and PGT. Fifty per cent (13/26) had a live birth child and 19% (5/26) are currently pregnant. Six couples (10%; 6/32) have pending tests. Among patients who decided not to proceed with PGT (31/63), the main reason for not doing so was that they had a spontaneous pregnancy before the first PGT cycle (35%; 11/31). Low ovarian reserve and couple´s refusal to proceed with PGT were the second most common reasons, each accounting for 22.5% of cases. In 10% (3/31) of cases, the indication for PGT was not yet approved in Spain (mainly because these patients already had a healthy living child). Maternal age over 40 years and the age of the prospective father were the reasons for not performing PGT in 6% and 3% respectively. Of note, a patient with ADPKD presented with a ruptured hepatic cyst after ovarian hormone stimulation. Therefore, PGT was discontinued after two cycles. Conclusion Women with IKD are most likely to request PGT than affected males. The most frequent condition is, by far, ADPKD. Once the technique is explained less than 50% of couples keep wishing to undergo PGT. Low ovarian reserve (which correlates quite well with age) is an important reason that impedes to go through PGT. Larger international studies are needed to understand the patient's uptake of PGT for IKD as well as the access to this technique depending on the country.

Genetic etiology of agenesis of the corpus callosum: a retrospective single-center cohort analysis of 114 fetuses.

The identification and prognosis of the agenesis of the corpus callosum (ACC) for prenatal consultation are complex and currently unclear. This study aims to explore the correlated genetic mutations of prenatal ACC. We retrospectively analyzed 114 prenatal cases of ACC. All cases (n = 114) were subjected to chromosomal microarray analysis (CMA), and 66 CMA-negative cases underwent prenatal exome sequencing (pES) for further analysis. CMA was diagnosed positively in 15/114 (13.2%) cases and pES was diagnosed positively in 24/66 (36.4%) CMA-negative cases. The detection rate of genetic causes between complete and partial ACCs was not significantly different (P > 0.05). Between isolated and non-isolated (other anomalies present) ACCs, the diagnostic rate of pES in non-isolated cases was significantly higher (P < 0.001), while CMA results did not differ (P > 0.05). The diagnostic rate of CMA was significantly increased in cases combined with intracranial and extracranial malformations (P = 0.014), while no CMA positivity was detected in cases combined with only intracranial malformations. For fetuses with prenatal ACC, further pES analysis should be recommended after negative CMA results. Chromosome abnormalities are less likely to occur when ACC with only intracranial malformations combined.

Connexin channels and hemichannels are modulated differently by charge reversal at residues forming the intracellular pocket

BackgroundMembers of the β-subfamily of connexins contain an intracellular pocket surrounded by amino acid residues from the four transmembrane helices. The presence of this pocket has not previously been investigated in members of the α-, γ-, δ-, and ε-subfamilies. We studied connexin50 (Cx50) as a representative of the α-subfamily, because its structure has been determined and mutations of Cx50 are among the most common genetic causes of congenital cataracts.MethodsTo investigate the presence and function of the intracellular pocket in Cx50 we used molecular dynamics simulation, site-directed mutagenesis, gap junction tracer intercellular transfer, and hemichannel activity detected by electrophysiology and by permeation of charged molecules.ResultsEmploying molecular dynamics, we determined the presence of the intracellular pocket in Cx50 hemichannels and identified the amino acids participating in its formation. We utilized site-directed mutagenesis to alter a salt-bridge interaction that supports the intracellular pocket and occurs between two residues highly conserved in the connexin family, R33 and E162. Substitution of opposite charges at either position decreased formation of gap junctional plaques and cell–cell communication and modestly reduced hemichannel currents. Simultaneous charge reversal at these positions produced plaque-forming non-functional gap junction channels with highly active hemichannels.ConclusionsThese results show that interactions within the intracellular pocket influence both gap junction channel and hemichannel functions. Disruption of these interactions may be responsible for diseases associated with mutations at these positions.

#821 Kibra mediates the activation of hippo by classic signal pathway related to NPHP1 defect

Abstract Background and Aims Nephronophthisis (NPH) is an autosomal recessive cystic kidney disease, which is the most common genetic cause of end-stage renal disease (ESRD) in children. The pathogenesis of NPH has not been clear yet. There are more than 20 different pathogenic genes identified at present, among which NPHP1 is the most prevalent one. Hippo signal pathway has been suggested to be involved in the pathogenesis of NPH cause by NPHP4 and NPHP9 defects, respectively. In the present study, we attempted to explore the state of hippo signal pathway in NPHP1 defect in both MDCK cells and C57/6j mice. Method NPHP1 knockout (NPHP1KO) MDCK cells and NPHP1KO C57BL/6J mice were constructed by CRISPR/Cas9 technology. Recombined kibra knockdown siRNA, kibra knockdown AAV9 (AAV9-Kibra-KD) and NPHP1 overexpress AAV9 construct (AAV9-NPHP1-OE) were constructed, respectively. The expression and phosphorylation of core molecules of hippo pathway in different group of MDCK cells and the kidney C57BL/6J mice were investigated through Real-time Quantitative PCR, western blotting, immunofluorescence. The renal pathology of the mice kidney was also observed. Results In NPHP1KO MDCK cells and the kidney of NPHP1KO mice, the expression of KIBRA, p-MST, p-LATS and p-Yap were increased, which indicates the activation of hippo signal pathway. The activation of hippo pathway could be suppressed partially by NPHP1 re-expression both in NPHP1KO MDCK cells and the kidney of NPHP1KO mice, which means the activation of hippo pathway was related to NPHP1 defect both in vitro and in vivo. Moreover, the kidney pathological changes were improved by NPHP1 re-expression. Kibra is the upper regulator of hippo signal pathway, we observed that kibra knockdown inhibited the activation of hippo pathway both in NPHP1KO MDCK cells and the kidney of NPHP1KO mice, which indicates that kibra mediates the activation of hippo pathway related to NPHP1 defect both in vitro and in vivo. As well, kibra knockdown ameliorated renal fibrosis CTGF expression, interstitial inflammation and renal cyst formation in NPHP1KO mice. Conclusion We conclude that NPHP1 defect activates hippo pathway which involves in the pathogenesis of NPH. Kibra mediates the activation of hippo related to NPHP1 defect by classic signal pathway. Hippo signal maybe a target for the treatment of NPHP1 defect NPH.

#1323 Kidney health in children with X-linked hypophosphatemia: lessons from the prospective multicenter study in Germany and Switzerland

Abstract Background and Aims X-linked hypophosphatemia (XLH) is the most common genetic cause of hypophosphatemia. Mutations in the PHEX gene cause elevated circulating levels of fibroblast growth factor 23 (FGF23), phosphaturia, rickets and osteomalacia. Conventional treatment with phosphate salts and active vitamin D is associated with nephrocalcinosis and preclinical studies in mice have shown that a chronic high phosphate load causes proximal tubular injury and fibrosis. There is no detailed analysis on kidney health in XLH patients yet. Method We conduct a prospective observational multicenter study in Germany and Switzerland to evaluate kidney health in pediatric XLH patients. Patients receive conventional therapy or burosumab, a fully humanized anti-FGF23 antibody. Clinical and biochemical data, blood and urine samples are collected annually. Results To date, 137 patients (80 girls, mean age 10.5 years) from 40 centers are included. 22% of patients have been treated conventionally for 7.5 years, 78% of patients have received burosumab for 2.3 years with 3.7 years of conventional therapy beforehand. Children with XLH show increased systolic blood pressure and body mass index (BMI), and overweight (BMI &amp;gt;90th percentile) and hypertension (systolic blood pressure &amp;gt;95th percentile) were each found in 20% of patients. A reduced eGFR (&amp;lt;90 ml/min/1.73 m2) and/or nephrocalcinosis was noted in 7% and 28% of patients, respectively. Microalbuminuria is twice as prevalent in children with XLH as in healthy children (14% vs 7%). Urinary lithogenic substances (calcium, oxalate, glycolate) are increased in 1.8-22.8%, and citrate is decreased in 12.3% of XLH patients. Tubular injury markers neutrophil gelatinase-associated lipocalin (NGAL) and Dickkopf-3 (DKK3) are elevated in urine of children with XLH, Chitinase 3-like 1 (CHl3L1) is comparable to children with chronic kidney disease, while kidney injury molecule-1 (Kim-1), indicating proximal tubule cell injury, is within a normal range. The renal inflammation marker monocyte chemoattractant protein-1 (MCP-1) is elevated in children with XLH, and epidermal growth factor (EGF), a marker of tubular cell repair, is decreased compared to healthy adults. Conclusion Pediatric XLH patients on conventional or burosumab therapy show enhanced systolic blood pressure slightly associated with elevated BMI, and significant renal comorbidity, i.e. reduced eGFR, nephrocalcinosis, increased urinary lithogenic substances, elevated urinary markers of glomerular and tubular injury and inflammation. The impact of conventional versus burosumab treatment are still being investigated.

Exome sequencing in four families with neurodevelopmental disorders: genotype-phenotype correlation and identification of novel disease-causing variants in VPS13B and RELN.

Neurodevelopmental disorders (NDDs) are a clinically and genetically heterogeneous group of early-onset pediatric disorders that affect the structure and/or function of the central or peripheral nervous system. Achieving a precise molecular diagnosis for NDDs may be challenging due to the diverse genetic underpinnings and clinical variability. In the current study, we investigated the underlying genetic cause(s) of NDDs in four unrelated Pakistani families. Using exome sequencing (ES) as a diagnostic approach, we identified disease-causing variants in established NDD-associated genes in all families, including one hitherto unreported variant in RELN and three recurrent variants in VPS13B, DEGS1, and SPG11. Overall, our study highlights the potential of ES as a tool for clinical diagnosis.

Analysis of copy number variants detected by sequencing in spontaneous abortion.

The incidence of spontaneous abortion (SA), which affects approximately 15-20% of pregnancies, is the most common complication of early pregnancy. Pathogenic copy number variations (CNVs) are recognized as potential genetic causes of SA. However, CNVs of variants of uncertain significance (VOUS) have been identified in products of conceptions (POCs), and their correlation with SA remains uncertain. Of 189 spontaneous abortion cases, trisomy 16 was the most common numerical chromosome abnormality, followed by monosomy X. CNVs most often occurred on chromosomes 4 and 8. Gene Ontology and signaling pathway analysis revealed significant enrichment of genes related to nervous system development, transmembrane transport, cell adhesion, and structural components of chromatin. Furthermore, genes within the VOUS CNVs were screened by integrating human placental expression profiles, PhyloP scores, and Residual Variance Intolerance Score (RVIS) percentiles to identify potential candidate genes associated with spontaneous abortion. Fourteen potential candidate genes (LZTR1, TSHZ1, AMIGO2, H1-4, H2BC4, H2AC7, H3C8, H4C3, H3C6, PHKG2, PRR14, RNF40, SRCAP, ZNF629) were identified. Variations in LZTR1, TSHZ1, and H4C3 may contribute to embryonic lethality. CNV sequencing (CNV-seq) analysis is an effective technique for detecting chromosomal abnormalities in POCs and identifying potential candidate genes for SA.

Simultaneous Detection of Common Founder Mutations Using a Cost-Effective Deep Sequencing Panel.

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of diseases which cause visual loss due to Mendelian mutations in over 250 genes, making genetic diagnosis challenging and time-consuming. Here, we developed a new tool, CDIP (Cost-effective Deep-sequencing IRD Panel) in which a simultaneous sequencing of common mutations is performed. CDIP is based on simultaneous amplification of 47 amplicons harboring common mutations followed by next-generation sequencing (NGS). Following five rounds of calibration of NGS-based steps, CDIP was used in 740 IRD samples. The analysis revealed 151 mutations in 131 index cases. In 54 (7%) of these cases, CDIP identified the genetic cause of disease (the remaining were single-heterozygous recessive mutations). These include a patient that was clinically diagnosed with retinoschisis and found to be homozygous for NR2E3-c.932G>A (p.R311Q), and a patient with RP who is hemizygous for an RPGR variant, c.292C>A (p.H98N), which was not included in the analysis but is located in proximity to one of these mutations. CDIP is a cost-effective deep sequencing panel for simultaneous detection of common founder mutations. This protocol can be implemented for additional populations as well as additional inherited diseases, and mainly in populations with strong founder effects.

Macrocephaly and Finger Changes: A Narrative Review

Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians. This review aims to provide a current synthetic overview of the main acquired and genetic etiologies associated with macrocephaly and finger changes. The genetic cause encompasses several categories of diseases, including bone marrow expansion disorders, skeletal dysplasias, ciliopathies, inherited metabolic diseases, RASopathies, and overgrowth syndromes. Furthermore, autoimmune and autoinflammatory diseases are also explored for their potential involvement in macrocephaly and finger changes. The intricate genetic mechanisms involved in the formation of cranial bones and extremities are multifaceted. An excess in growth may stem from disruptions in the intricate interplays among the genetic, epigenetic, and hormonal factors that regulate human growth. Understanding the underlying cellular and molecular mechanisms is important for elucidating the developmental pathways and biological processes that contribute to the observed clinical phenotypes. The review provides a practical approach to delineate causes of macrocephaly and finger changes, facilitate differential diagnosis and guide for the appropriate etiological framework. Early recognition contributes to timely intervention and improved outcomes for affected individuals.

Hematophagocytic Syndrome in a Patient Co-Infected With HIV: A Case Report

Introduction: Hemophagocytic syndrome is a severe disease characterized by a state of systemic hyperinflammation with overproduction of cytokines. It can respond to genetic causes (primary) or be triggered by infections, drugs, neoplasms or autoimmune diseases. With increased mortality. We present the case of a patient with HIV who developed hemophagocytic syndrome during hospitalization. Case presentation: We present the case of a male patient with human immunodeficiency virus who developed hemophagocytic syndrome with lymphadenopathies and biopsy report concluding the syndromic suspicion. Conclusions: Our case report reflects the clinical and biochemical approach to hemophagocytic syndrome, in which the realization of a histopathological diagnosis was determinant to reflect the cause of the disease in question, we denote the importance of clinical suspicion in infrequent situations related to the patient with immunodeficiency.