Aleksander Jamsheer

Congenital vertebral malformations (CVMs), affecting approximately 0.5–1 per 1000 live births, occur either in an isolated form or as part of syndromic disorders. Despite the identification of numerous causative genes for CVMs, the molecular etiology of most cases remains unknown. In this study, we applied a three-tiered diagnostic approach (chromosomal microarray analysis, followed by custom gene panel analysis, and exome/genome sequencing) in a cohort of 34 patients with CVMs. We achieved a 12% diagnostic success rate, identifying a deletion upstream of SOX9 and pathogenic or likely pathogenic variants in FLNB and KMT2D. Most pathogenic variants were detected by exome or genome sequencing, while earlier-tier analyses yielded limited results. We also identified two candidate genes, NSD2 and TBXT, that may contribute to the phenotype observed in our patients, but warrant future functional validation. Our work expands the molecular spectrum of CVMs and highlights the utility of comprehensive genomic testing for improving diagnosis and understanding of vertebral development disorders.

Acute lymphoblastic leukemia (ALL) is the most frequent malignancy in children. Although survival rates have improved in recent decades, relapse and therapy-related toxicities remain major challenges in pediatric ALL. Pharmacogenetics is an approach with the potential to refine precision medicine in pediatric ALL. This review synthesizes current knowledge on pharmacogenetic markers of drug efficacy, toxicity, and adverse effects for drugs used in childhood ALL, including glucocorticosteroids, vincristine, asparaginase, anthracyclines, 6-mercaptopurine, and methotrexate. Thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) are the only pharmacogenetic markers with established clinical guidelines that inform thiopurine and methotrexate dosing. Insufficient and inconsistent evidence has limited the translation of most other pharmacogenetic findings into clinical practice. While most studies centered on coding variants, we also point to new approaches focusing on noncoding regions and epigenetic variation that hold promise for expanding the scope of clinically relevant biomarkers in the near future. Finally, we propose future research avenues, that could support the development of more individualized treatment strategies for children with ALL.

Background: Campomelic dysplasia (CD) is a rare congenital skeletal dysplasia frequently associated with differences of sex development (DSD). In about 10% of affected individuals, the bowing of the long bones (campomelia) is absent, referred to as acampomelic campomelic dysplasia (ACD). Most patients with ACD carry heterozygous pathogenic variants within the SOX9 coding region or balanced chromosomal rearrangements involving the 17q24 region. A rarer mechanism involves deletions located upstream of the SOX9 gene. Only five ACD cases with upstream deletions of SOX9 have been reported in the medical literature. Results: We report a female patient affected by ACD with Pierre Robin sequence, complete gonadal dysgenesis (CGD), and hypotonia. Genetic testing revealed a de novo 1.671 Mb deletion located 191 kb upstream of the SOX9 gene. This chromosomal aberration represents the second-largest deletion upstream of SOX9 reported to date. In addition, we describe the patient’s endocrine profile, which revealed an absent gonadotropin rise during minipuberty, followed by a delayed increase in infancy. Conclusions: This study expands the clinical and molecular spectrum of ACD, enhancing our understanding of genotype-phenotype correlations of this condition. The phenotypic and endocrinological description of the proband may be helpful for clinicians who consult patients with DSD and skeletal dysplasia.

Background/Objectives: Neurodevelopmental disorders (NDDs) are genetically heterogeneous conditions with a complex molecular etiology involving numerous genes. Biallelic pathogenic variants in INTS1 cause a rare autosomal recessive NDD characterized by congenital cataracts, growth retardation, facial dysmorphism, and global developmental delay. To date, the clinical description of this disorder has been based solely on individual case reports, and its phenotypic spectrum remains incompletely defined. Methods: A 9-year-old female proband was evaluated for developmental delay, multiple congenital anomalies, and distinctive craniofacial features. Whole-exome sequencing (WES) was performed, followed by Sanger validation and segregation analysis. Variant pathogenicity was assessed using in silico prediction tools and 3D protein structural modeling. Results: Whole-exome sequencing identified two novel compound heterozygous missense variants in INTS1, c.1145G>A (p.Arg382Gln) and c.1195G>A (p.Gly399Ser), both located in exon 9. Segregation analysis showed that c.1145G>A was inherited from the father and c.1195G>A from the mother, and both variants are extremely rare in population databases. Conclusions: We report a patient carrying novel biallelic INTS1 variants, whose clinical presentation differs from previously reported cases, including those with milder phenotypes characterized by preserved speech development and absence of intellectual disability. This observation broadens the clinical spectrum of INTS1-related disease and underscores its phenotypic heterogeneity.

Background: Split-hand/foot malformation (SHFM) is a rare congenital limb anomaly defined by the absence or hypoplasia of the central rays of the autopod. SHFM occurs as an isolated entity or part of genetic syndromes with several causative copy-number variations or monogenic alterations known to be involved in the disease pathomechanism. On the other hand, cleft lip/palate (CL/P) usually results from polygenic and environmental factors, with the complex interplay of both leading to this malformation. Pathogenic variants in FGFR1 have been linked to phenotypically distinct disorders, including Hartsfield syndrome, Kallmann syndrome, Jackson–Weiss syndrome, osteoglophonic dysplasia, and Pfeiffer syndrome. Although pathogenic variants in FGFR1 can contribute to syndromic SHFM or CL/P, their role in isolated SHFM or CL remains poorly described in the literature. Methods: We conducted targeted next-generation sequencing (NGS) in the proband with SHFM, followed by segregation analysis in the family members. Results: In this study, we report an index patient presenting with isolated SHFM and his brother with CL and facial dysmorphism, as well as their father with isolated hyposmia. Targeted next-generation sequencing revealed a previously reported heterozygous missense pathogenic variant in FGFR1 (c.830G>A; p.Cys277Tyr) in both affected siblings and their hyposmic father. Conclusions: This study expands the phenotypic spectrum associated with FGFR1 pathogenic variants, emphasizing their involvement in non-syndromic SHFM and CL or isolated hyposmia. Our findings highlight the importance of considering FGFR1 in the molecular diagnosis of isolated SHFM or orofacial clefting, point to the high intrafamilial variability of FGFR1 pathogenic variants, and demonstrate the diagnostic value of targeted NGS in rare congenital malformations.

Fibrodysplasia ossificans progressiva (FOP; OMIM #135100) is a rare genetic disorder characterized by congenital malformation of the great toes and progressive heterotopic ossification of soft tissues. To date, the disease has been linked to 15 pathogenic variants in the ACVR1 gene, which encodes a type I receptor for bone morphogenetic proteins. Most patients with FOP carry a recurrent single-nucleotide substitution (c.617G>A; p.Arg206His) in the ACVR1 gene. The genotype–phenotype correlations for atypical pathogenic variants of ACVR1 are poorly understood. In this study, we report the largest population of Polish patients affected by FOP and analyze their phenotypes and genotypes. We screened the whole ACVR1 coding sequence of 16 patients affected by FOP to confirm the presence of pathogenic variants. Thirteen individuals carried the classic pathogenic variant (p.Arg206His) and had a classic or FOP-plus phenotype. In agreement with the findings of previous studies, one patient with a p.Gly356Asp pathogenic variant had a variant FOP phenotype. We point to an unusual phenomenon in two patients who carried atypical pathogenic variants (p.Gly356Asp and p.Arg258Ser) and displayed a classic FOP phenotype. Our study extends the understanding of FOP’s genotype–phenotype correlation, suggesting that classic FOP phenotypes are associated with non-classic pathogenic variants. We also summarize the recent advances in drug development for this condition. Therefore, the study may be valuable for clinicians consulting patients with FOP.

The COVID-19 pandemic has profoundly affected all aspects of our lives. Through real-time monitoring and rapid vaccine implementation, we succeeded in suppressing the spread of the disease and mitigating its consequences. Finally, conclusions can be summarized and drawn. Here, we use the example of Poland, which was seriously affected by the pandemic. Compared to other countries, Poland has not achieved impressive results in either testing or vaccination, which may explain its high mortality (case fatality rate, CFR 1.94%). Through retrospective analysis of data collected by the COVID-19 Data Portal Poland, we found significant regional differences in the number of tests performed, number of cases detected, number of COVID-19-related deaths, and vaccination rates. The Masovian, Greater Poland, and Pomeranian voivodeships, the country’s leaders in vaccination, reported high case numbers but low death rates. In contrast, the voivodeships in the eastern and southern parts of Poland (Subcarpathian, Podlaskie, Lublin, Opole), which documented low vaccination levels and low case numbers, had higher COVID-19-related mortality rates. The strong negative correlation between the CFR and the percentage of the population that was vaccinated in Poland supports the validity of vaccination. To gain insight into virus evolution, we sequenced more than 500 genomes and analyzed nearly 80 thousand SARS-CoV-2 genome sequences deposited in GISAID by Polish diagnostic centers. We showed that the SARS-CoV-2 variant distribution over time in Poland reflected that in Europe. Haplotype network analysis allowed us to follow the virus transmission routes and identify potential superspreaders in each pandemic wave.

Vertebral malformations (VMs) pose a significant global health problem, causing chronic pain and disability. Vertebral defects occur as isolated conditions or within the spectrum of various congenital disorders, such as Klippel–Feil syndrome, congenital scoliosis, spondylocostal dysostosis, sacral agenesis, and neural tube defects. Although both genetic abnormalities and environmental factors can contribute to abnormal vertebral development, our knowledge on molecular mechanisms of numerous VMs is still limited. Furthermore, there is a lack of resource that consolidates the current knowledge in this field. In this pioneering review, we provide a comprehensive analysis of the latest research on the molecular basis of VMs and the association of the VMs-related causative genes with bone developmental signaling pathways. Our study identifies 118 genes linked to VMs, with 98 genes involved in biological pathways crucial for the formation of the vertebral column. Overall, the review summarizes the current knowledge on VM genetics, and provides new insights into potential involvement of biological pathways in VM pathogenesis. We also present an overview of available data regarding the role of epigenetic and environmental factors in VMs. We identify areas where knowledge is lacking, such as precise molecular mechanisms in which specific genes contribute to the development of VMs. Finally, we propose future research avenues that could address knowledge gaps.

Chromatinopathies (CPs), a group of rare inborn defects characterized by chromatin state imbalance, have evolved from initially resembling Cornelia de Lange syndrome to encompass a wide array of genetic diseases with diverse clinical presentations. The CPs classification now includes human developmental disorders caused by germline mutations in epigenes, genes that regulate the epigenome. Recent advances in next-generation sequencing have enabled the association of 154 epigenes with CPs, revealing distinctive DNA methylation patterns known as episignatures.It has been shown that episignatures are unique for a particular CP or share similarities among specific CP subgroup. Consequently, these episignatures have emerged as promising biomarkers for diagnosing and treating CPs, differentiating subtypes, evaluating variants of unknown significance, and facilitating targeted therapies tailored to the underlying epigenetic dysregulation.The following review was conducted to collect, summarize, and analyze data regarding CPs in such aspects as clinical evaluation encompassing long-term patient care, underlying epigenetic changes, and innovative molecular and bioinformatic methodologies that have been devised for the assessment of CPs. We have also shed light on promising novel treatment options that have surfaced in recent research and presented a synthesis of ongoing clinical trials, contributing to the current understanding of the dynamic and evolving nature of CPs investigation.