Genetic determinants of global developmental delay and intellectual disability in Ukrainian children.

BACKGROUND: Global developmental delay or intellectual disability usually accompanies various genetic disorders as a part of the syndrome, which may include seizures, autism spectrum disorder and multiple congenital abnormalities. Next-generation sequencing (NGS) techniques have improved the identification of pathogenic variants and genes related to developmental delay. This study aimed to evaluate the yield of whole exome sequencing (WES) and neurodevelopmental disorder gene panel sequencing in a pediatric cohort from Ukraine. Additionally, the study computationally predicted the effect of variants of uncertain significance (VUS) based on recently published genetic data from the country's healthy population. METHODS: The study retrospectively analyzed WES or gene panel sequencing findings of 417 children with global developmental delay, intellectual disability, and/or other symptoms. Variants of uncertain significance were annotated using CADD-Phred and SIFT prediction scores, and their frequency in the healthy population of Ukraine was estimated. RESULTS: A definitive molecular diagnosis was established in 66 (15.8%) of the individuals. WES diagnosed 22 out of 37 cases (59.4%), while the neurodevelopmental gene panel identified 44 definitive diagnoses among the 380 tested patients (12.1%). Non-diagnostic findings (VUS and carrier) were reported in 350 (83.2%) individuals. The most frequently diagnosed conditions were developmental and epileptic encephalopathies associated with severe epilepsy and GDD/ID (associated genes ARX, CDKL5, STXBP1, KCNQ2, SCN2A, KCNT1, KCNA2). Additionally, we annotated 221 VUS classified as potentially damaging, AD or X-linked, potentially increasing the diagnostic yield by 30%, but 18 of these variants were present in the healthy population of Ukraine. CONCLUSIONS: This is the first comprehensive study on genetic causes of GDD/ID conducted in Ukraine. This study provides the first comprehensive investigation of the genetic causes of GDD/ID in Ukraine. It presents a substantial dataset of diagnosed genetic conditions associated with GDD/ID. The results support the utilization of NGS gene panels and WES as first-line diagnostic tools for GDD/ID cases, particularly in resource-limited settings. A comprehensive approach to resolving VUS, including computational effect prediction, population frequency analysis, and phenotype assessment, can aid in further reclassification of deleterious VUS and guide further testing in families.

Novel ABCD1 variant causes phenotype of adrenomyeloneuropathy with cerebral involvement in Ukrainian siblings: first adult hematopoietic stem cell transplantation for ALD in Ukraine: a case report.

BACKGROUND: This article presents a case study of two white male siblings of 24 and 31 years of age of self-reported Ukrainian ethnicity diagnosed with adrenomyeloneuropathy (AMN) associated with a novel splice site mutation in the ABCD1 gene. AMN represents a form of X-linked adrenoleukodystrophy (X-ALD) characterized by demyelination of the spinal cord and peripheral nerves. The case also presents the first adult haematopoietic stem cell transplant (HSCT) for adrenomyeloneuropathy in Ukraine. The rarity of this mutation and its cerebral involvement and the treatment make this case noteworthy and underscore the significance of reporting it to contribute to the existing medical knowledge. CASE PRESENTATION: The patients of 24 and 31 years initially exhibited progressive gait disturbance, lower extremity pain, and urinary incontinence, with the older sibling experiencing more advanced symptoms of speech, hearing, and vision disturbances. A comprehensive genetic analysis identified an unreported splice site mutation in exon 3 of the ABCD1 gene, leading to the manifestation of AMN. The inheritance pattern was consistent with X-linked recessive transmission. The article also outlines the clinical features, magnetic resonance imaging (MRI), and nerve conduction study (NCS) findings. Moreover, it discusses the genetic profile of the affected individuals and female carriers within the family. The younger sibling underwent HSCT, which was complicated by mediastinal lymph node and lung tuberculosis, adding to the complexity of managing adult ALD patients. CONCLUSIONS: This report emphasizes the importance of genetic testing in diagnosing and comprehending the underlying mechanisms of rare genetic disorders, such as AMN with cerebral involvement. The identification of a novel splice site mutation expands our understanding of the genetic landscape of this condition. Additionally, the challenges and complications encountered during the hematopoietic stem cell transplant procedure underscore the need for cautious consideration and personalized approaches in adult ALD patients.

Genetic diversity and selection in Puerto Rican horses.

Since the first Spanish settlers brought horses to America centuries ago, several local varieties and breeds have been established in the New World. These were generally a consequence of the admixture of the different breeds arriving from Europe. In some instances, local horses have been selectively bred for specific traits, such as appearance, endurance, strength, and gait. We looked at the genetics of two breeds, the Puerto Rican Non-Purebred (PRNPB) (also known as the "Criollo") horses and the Puerto Rican Paso Fino (PRPF), from the Caribbean Island of Puerto Rico. While it is reasonable to assume that there was a historic connection between the two, the genetic link between them has never been established. In our study, we started by looking at the genetic ancestry and diversity of current Puerto Rican horse populations using a 668 bp fragment of the mitochondrial DNA D-loop (HVR1) in 200 horses from 27 locations on the island. We then genotyped all 200 horses in our sample for the "gait-keeper" DMRT3 mutant allele previously associated with the paso gait especially cherished in this island breed. We also genotyped a subset of 24 samples with the Illumina Neogen Equine Community genome-wide array (65,000 SNPs). This data was further combined with the publicly available PRPF genomes from other studies. Our analysis show an undeniable genetic connection between the two varieties in Puerto Rico, consistent with the hypothesis that PRNPB horses represent the descendants of the original genetic pool, a mix of horses imported from the Iberian Peninsula and elsewhere in Europe. Some of the original founders of PRNRB population must have carried the "gait-keeper" DMRT3 allele upon arrival to the island. From this admixture, the desired traits were selected by the local people over the span of centuries. We propose that the frequency of the mutant "gait-keeper" allele originally increased in the local horses due to the selection for the smooth ride and other characters, long before the PRPF breed was established. To support this hypothesis, we demonstrate that PRNPB horses, and not the purebred PRPF, carry a signature of selection in the genomic region containing the DMRT3 locus to this day. The lack of the detectable signature of selection associated with the DMRT3 in the PRPF would be expected if this native breed was originally derived from the genetic pool of PRNPB horses established earlier and most of the founders already had the mutant allele. Consequently, selection specific to PRPF later focused on allels in other genes (including CHRM5, CYP2E1, MYH7, SRSF1, PAM, PRN and others) that have not been previously associated with the prized paso gait phenotype in Puerto Rico or anywhere else.

Scientists without borders: lessons from Ukraine.

Conflicts and natural disasters affect entire populations of the countries involved and, in addition to the thousands of lives destroyed, have a substantial negative impact on the scientific advances these countries provide. The unprovoked invasion of Ukraine by Russia, the devastating earthquake in Turkey and Syria, and the ongoing conflicts in the Middle East are just a few examples. Millions of people have been killed or displaced, their futures uncertain. These events have resulted in extensive infrastructure collapse, with loss of electricity, transportation, and access to services. Schools, universities, and research centers have been destroyed along with decades' worth of data, samples, and findings. Scholars in disaster areas face short- and long-term problems in terms of what they can accomplish now for obtaining grants and for employment in the long run. In our interconnected world, conflicts and disasters are no longer a local problem but have wide-ranging impacts on the entire world, both now and in the future. Here, we focus on the current and ongoing impact of war on the scientific community within Ukraine and from this draw lessons that can be applied to all affected countries where scientists at risk are facing hardship. We present and classify examples of effective and feasible mechanisms used to support researchers in countries facing hardship and discuss how these can be implemented with help from the international scientific community and what more is desperately needed. Reaching out, providing accessible training opportunities, and developing collaborations should increase inclusion and connectivity, support scientific advancements within affected communities, and expedite postwar and disaster recovery.

Genome diversity in Ukraine.

BACKGROUND: The main goal of this collaborative effort is to provide genome-wide data for the previously underrepresented population in Eastern Europe, and to provide cross-validation of the data from genome sequences and genotypes of the same individuals acquired by different technologies. We collected 97 genome-grade DNA samples from consented individuals representing major regions of Ukraine that were consented for public data release. BGISEQ-500 sequence data and genotypes by an Illumina GWAS chip were cross-validated on multiple samples and additionally referenced to 1 sample that has been resequenced by Illumina NovaSeq6000 S4 at high coverage. RESULTS: The genome data have been searched for genomic variation represented in this population, and a number of variants have been reported: large structural variants, indels, copy number variations, single-nucletide polymorphisms, and microsatellites. To our knowledge, this study provides the largest to-date survey of genetic variation in Ukraine, creating a public reference resource aiming to provide data for medical research in a large understudied population. CONCLUSIONS: Our results indicate that the genetic diversity of the Ukrainian population is uniquely shaped by evolutionary and demographic forces and cannot be ignored in future genetic and biomedical studies. These data will contribute a wealth of new information bringing forth a wealth of novel, endemic and medically related alleles.

Vitamin D status in adults and children in Transcarpathia, Ukraine in 2019.

BACKGROUND: Vitamin D deficiency is a global health problem, it is assessed by measuring serum 25-hydroxivitamin D (25(OH) D), nevertheless epidemiological data for many countries remains underreported. OBJECTIVES: To study the prevalence of vitamin D deficiency throughout the calendar year in a large cohort recruited ina multiethnic Transcarpathian region of Ukraine. METHODS: In this retrospective study 25(OH) D serum concentration was measured during all 12 months of the year 2019 by electrochemoluminescent assay on the automatic analyzer Cobas e411 in 1823 subjects, including both children and adults (1551 females (85.03%) and 273 males (14.97%)). RESULTS: The mean 25(OH) D concentration in adults demonstrates significantly lower levels compared to children (22.67 ± 8.63 ng/ml vs. 26.00 ± 10.72 ng/ml respectively, p < 0.001). Adult women expressed significantly lower mean annual serum 25 (OH) D concentrations in comparison to men (22.29 ± 8.46 ng/ml vs. 25.75 ± 9.38 ng/ml respectively, p < 0.001). In contrast, children did not show a significant difference between sexes (girls 24.98 ± 10.38 ng/ml vs. boys 27.01 ± 11.01 ng/ml, p = 0.2003). In the winter months, 25(OH) D levels fell below 20 ng/ml in 51,74% of adult population of Thranscarpathia, and in 12.91%, - below 12 ng/ml. CONCLUSIONS: The results of this study contradict the previously reported evaluations of the vitamin D levels in Ukraine which were assessed by measuring serum 25(OH) D. Specifically, only approximately half of the studied population is vitamin D deficient during winter season. This study features the most representative sample size in Ukraine to date.