Identifying Genomic Signatures of Positive Selection to Predict Protective Genomic Loci in the Cohort of Lithuanian Clean-Up Workers of the Chornobyl Nuclear Disaster.

Some people resist or recover from health challenges better than others. We studied Lithuanian clean-up workers of the Chornobyl nuclear disaster (LCWC) who worked in the harshest conditions and, despite high ionising radiation doses as well as other factors, continue ageing relatively healthily. Thus, we hypothesised that there might be individual features encoded by the genome which act protectively for better adaptiveness and health that depend on unique positive selection signatures. Whole-genome sequencing was performed for 40 LCWC and a control group composed of 25 men from the general Lithuanian population (LTU). Selective sweep analysis was performed to identify genomic regions which may be under recent positive selection and determine better adaptiveness. Twenty-two autosomal loci with the highest positive selection signature values were identified. Most important, unique loci under positive selection have been identified in the genomes of the LCWC, which may influence the survival and adaptive qualities to extreme conditions, and the disaster itself. Characterising these loci provide a better understanding of the interaction between ongoing microevolutionary processes, multifactorial traits, and diseases. Studying unique groups of disease-resistant individuals could help create new insights for better, more individualised, disease diagnostics and prevention strategies.

Causes of preterm birth: Genetic factors in preterm birth and preterm infant phenotypes.

AIM: The aim is to provide an overview of recent research on genetic factors that influence preterm birth in the context of neonatal phenotypic assessment. METHODS: This is a nonsystematic review of the recent scientific literature. RESULTS: Maternal and fetal genetic diversity and rare genome variants are linked with crucial immune response sites. In addition, more frequent in preterm neonates, de novo variants may lead to attention deficits, hyperactivity, autism spectrum disorders, and infertility of both sexes later in life. Environmental factors may also greatly burden fetal, and consequently, neonatal development and neurodevelopment through a failure in the fetal epigenome reprogramming process and even influence the initiation of spontaneous preterm pregnancy termination. Minimally invasive analysis of the transcription factors associated with preterm birth helps elucidate labor mechanisms and predict its timing. We also provide valuable summaries of genomic and transcriptomic factors that contribute to preterm birth. CONCLUSIONS: Investigation of the human genome, epigenome, and transcriptome helps to identify molecular mechanisms linked with preterm delivery and premature newborn clinical appearance in early and late neonatal life and even predict developmental outcomes. Further studies are needed to fully understand the implications of genetic changes in preterm births. These data could be used to develop targeted interventions aimed at selecting the most effective individual treatment and rehabilitation plan.

A novel variant in the PDE4D gene is the cause of Acrodysostosis type 2 in a Lithuanian patient: a case report.

BACKGROUND: Acrodysostosis is a rare hereditary disorder described as a primary bone dysplasia with or without hormonal resistance. Pathogenic variants in the PRKAR1A and PDE4D genes are known genetic causes of this condition. The latter gene variants are more frequently identified in patients with midfacial and nasal hypoplasia and neurological involvement. The aim of our study was to analyse and confirm a genetic cause of acrodysostosis in a male patient. CASE PRESENTATION: We report on a 29-year-old Lithuanian man diagnosed with acrodysostosis type 2. The characteristic phenotype includes specific skeletal abnormalities, facial dysostosis, mild intellectual disability and metabolic syndrome. Using patient's DNA extracted from peripheral blood sample, the novel, likely pathogenic, heterozygous de novo variant NM_001104631.2:c.581G > C was identified in the gene PDE4D via Sanger sequencing. This variant causes amino acid change (NP_001098101.1:p.(Arg194Pro)) in the functionally relevant upstream conserved region 1 domain of PDE4D. CONCLUSIONS: This report further expands the knowledge of the consequences of missense variants in PDE4D that affect the upstream conserved region 1 regulatory domain and indicates that pathogenic variants of the gene PDE4D play an important role in the pathogenesis mechanism of acrodysostosis type 2 without significant hormonal resistance.

The high frequency of GJB2 gene mutation c.313_326del14 suggests its possible origin in ancestors of Lithuanian population.

BACKGROUND: Congenital hearing loss (CHL) is diagnosed in 1 - 2 newborns in 1000, genetic factors contribute to two thirds of CHL cases in industrialised countries. Mutations of the GJB2 gene located in the DFNB1 locus (13q11-12) are a major cause of CHL worldwide. The aim of this cross-sectional study was to assess the contribution of the DFNB1 locus containing the GJB2 and GJB6 genes in the development of early onset hearing loss in the affected group of participants, to determine the population-specific mutational profile and DFNB1-related HL burden in Lithuanian population. METHODS: Clinical data were obtained from a collection of 158 affected participants (146 unrelated probands) with early onset non-syndromic HL. GJB2 and GJB6 gene sequencing and GJB6 gene deletion testing were performed. The data of GJB2 and GJB6 gene sequencing in 98 participants in group of self-reported healthy Lithuanian inhabitants were analysed. Statistic summary, homogeneity tests, and logistic regression analysis were used for the assessment of genotype-phenotype correlation. RESULTS: Our findings show 57.5% of affected participants with two pathogenic GJB2 gene mutations identified. The most prevalent GJB2 mutations were c.35delG, p. (Gly12Valfs*2) (rs80338939) and c.313_326del14, p. (Lys105Glyfs*5) (rs111033253) with allele frequencies 64.7% and 28.3% respectively. GJB6 gene mutations were not identified in the affected group of participants. The statistical analysis revealed significant differences between GJB2(-) and GJB2(+) groups in disease severity (p = 0.001), and family history (p = 0.01). The probability of identification of GJB2 mutations in patients with various HL characteristics was estimated. The carrier rate of GJB2 gene mutations - 7.1% (~1 in 14) was identified in the group of healthy participants and a high frequency of GJB2-related hearing loss was estimated in our population. DISCUSSION: The results show a very high proportion of GJB2-positive individuals in the research group affected with sensorineural HL. The allele frequency of c.35delG mutation (64.7 %) is consistent with many previously published studies in groups of affected individuals of Caucasian populations. The high frequency of the c.313_326del14 (28.3 % of pathogenic alleles) mutation in affected group of participants was an unexpected finding in our study suggesting not only a high frequency of carriers of this mutation in our population but also its possible origin in Lithuanian ancestors. The high frequency of carriers of the c.313_326del14 mutation in the entire Lithuanian population is supported by it being identified twice in the ethnic Lithuanian group of healthy participants (a frequency 2.0 % of carriers in the study group). CONCLUSION: Analysis of the allele frequency of GJB2 gene mutations revealed a high proportion of c. 313_326del14 (rs111033253) mutations in the GJB2-positive group suggesting its possible origin in Lithuanian forebears. The high frequency of carriers of GJB2 gene mutations in the group of healthy participants corresponds to the substantial frequency of GJB2-associated HL in Lithuania. The observations of the study indicate the significant contribution of GJB2 gene mutations to the pathogenesis of the disorder in the Lithuanian population and will contribute to introducing principles to predict the characteristics of the disease in patients.

Robust genotyping tool for autosomal recessive type of limb-girdle muscular dystrophies.

BACKGROUND: Limb-girdle muscular dystrophies are characterized by predominant involvement of the shoulder and pelvic girdle and trunk muscle groups. Currently, there are 31 genes implicated in the different forms of limb-girdle muscular dystrophies, which exhibit similar phenotypes and clinical overlap; therefore, advanced molecular techniques are required to achieve differential diagnosis. METHODS: We investigated 26 patients from Latvia and 34 patients from Lithuania with clinical symptoms of limb-girdle muscular dystrophies, along with 565 healthy unrelated controls from general and ethnic populations using our developed test kit based on the Illumina VeraCode GoldenGate genotyping platform, Ion AmpliSeq Inherited Disease Panel and direct sequencing of mutations in calpain 3 (CAPN3), anoctamin 5 (ANO5) and fukutin related protein (FKRP) genes. RESULTS: Analysis revealed a homozygous CAPN3 c.550delA mutation in eight patients and three heterozygous variants in controls: dysferlin (DYSF) c.5028delG, CAPN3 c.2288A > G, and FKRP c.135C > T. Additionally, three mutations within FKRP gene were found: homozygous c.826C > A, and two compound - c.826C > A/c.404_405insT and c.826C > A/c.204_206delCTC mutations, and one mutation within CLCN1 gene - c.2680C > T p.Arg894Ter. ANO5 c.191dupA was not present. CONCLUSIONS: Genetic diagnosis was possible in 12 of 60 patients (20%). The allele frequency of CAPN3 gene mutation c.550delA in Latvia is 0.0016 and in Lithuania - 0.0029. The allele frequencies of CAPN3 gene mutation c.2288A > G and DYSF gene mutation c.4872delG are 0.003.

Neuropsychiatric Aspects of Sotos Syndrome: Explorative Review Building Multidisciplinary Bridges in Clinical Practice.

Background: Sotos syndrome is a genetic disorder caused by NSD1 gene (nuclear receptor binding SET domain containing protein 1) variants and characterized by overgrowth, macrocephaly, learning disabilities, and co-occurring neuropsychiatric symptoms. Methods: Literature sources published in 2002-2023 were selected and analyzed from PubMed and Google Scholar databases. Results: Neuropsychiatric symptoms are observed among children and adolescents with Sotos syndrome. The majority have intellectual disabilities or borderline intellect. Verbal IQ is higher than performance IQ. Individuals display difficulties in expressing language. Aggression is reported by parents. Children express autistic behavior, ADHD, anxiety based on phobias, and early bedtime-wake times. Conclusions: Sotos syndrome is associated with neuropsychiatric disorders in children. Slow intellectual and language development, aggressive outbursts, anxiety, autism spectrum disorder, and hyperactivity are present in the newest studies. Comprehensive assistance is needed for Sotos syndrome patients in responding to areas of difficulty. There is still a lack of research on the developmental characteristics of these children and the possibilities of improving psychosocial adaptation by providing multidisciplinary long-term medical, educational, and social care.

Heterogeneity of oral clefts in relation to associated congenital anomalies.

BACKGROUND AND OBJECTIVE: The first step in the search for the genetic basis of oral clefts should be the well-accepted classification and clinical data protocols, which are important in distinguishing separate phenotypic groups. The aim of this study was to compare the frequency of congenital malformations associated with oral clefts between the different groups of oral clefts. MATERIAL AND METHODS: The study population comprised 238 patients with oral clefts and one or more major congenital anomalies. All cases of oral clefts were subdivided into 2 groups: patients with the recognized conditions (n=97, 40.8%) and patients with the multiple congenital anomalies of unknown origin (n=141, 59.2%). The frequency of associated congenital anomalies was compared between the cleft palate (CP) and cleft lip and/or palate (CL/P) groups as well as between the cleft lip only (CL) and cleft lip with cleft palate (CLP) subgroups. RESULTS: A total of 420 anomalies associated with oral clefts were diagnosed in 141 patients with multiple congenital anomalies (2.98 anomalies per proband) with the highest incidence being in the CP group (3.5 anomalies per proband). Comparison of the CP and CL/P groups showed that some of associated congenital anomalies such as atresia and stenosis of the small intestine and micrognathia occurred significantly more often in the CP than CL/P group (2.1% vs. 0% and 3.5% vs. 1.1%; P<0.05). Meanwhile, comparison of the CL and CLP subgroups revealed accessory auricle, other specified anomalies of the ear, congenital anomalies of the circulatory system, and certain congenital musculoskeletal deformities of the spine to be more common in the CL than CLP group (5.1% and 0.5%, 11.9% and 5.1%, 3.4% and 0%, 3.4% and 0%, respectively; P<0.05). CONCLUSIONS: The highest incidence of associated congenital anomalies was in the CP group followed by the CL, CL/P, and CLP groups. Generally, the anomalies of the musculoskeletal system, cardiovascular system, and face including eye, ear, and neck were most common. The careful analysis of associated anomalies and cases of oral cleft subgroups with multiple congenital anomalies is helpful in identifying the etiologic entities and underscores the need for thorough evaluation and competent distinction of various types of oral clefts.

Consensus recommendations on chewing, swallowing and gastrointestinal problems in Phelan-McDermid syndrome.

Gastrointestinal (GI) problems are common in Phelan-McDermid syndrome (PMS). Chewing and swallowing difficulties, dental problems, reflux disease, cyclic vomiting, constipation, incontinence, diarrhoea, and nutritional deficiencies have been most frequently reported. Therefore, this review summarises current findings on GI problems and addresses the fundamental questions, which were based on parental surveys, of how frequent GI problems occur in PMS, what GI problems occur, what consequences (e.g., nutritional deficiencies) GI problems cause for individuals with PMS, and how GI problems can be treated in individuals with PMS. Our findings show that gastrointestinal problems have a detrimental effect on the health of people with PMS and are a significant burden for their families. Therefore, we advise evaluation for these problems and formulate care recommendations.

A Sporadic Case of COL1A1 Osteogenesis Imperfecta: From Prenatal Diagnosis to Outcomes in Infancy-Case Report and Literature Review.

Osteogenesis imperfecta (OI), also known as brittle bone disease, belongs to a rare heterogeneous group of inherited connective tissue disorders. In experienced prenatal centers, severe cases of OI can be suspected before birth from the first trimester prenatal ultrasound screening. In this article, we describe a case report of OI suspected at the 26th week of gestation and the patient's outcomes in infancy one year after birth, as well as compare our case to other prenatally or soon-after-birth suspected and/or diagnosed OI clinical case reports in the literature. This case was managed by a multidisciplinary team. In this clinical case, OI was first suspected when prenatal ultrasound revealed asymmetric intrauterine growth restriction and skeletal dysplasia features. The diagnosis was confirmed after birth using COL1A1 gene variant detection via exome sequencing; the COL1A1 gene variant causes OI types I-IV. The familial history was negative for both pregnancy-related risk factors and genetic diseases. At one year old, the patient's condition remains severe with bisphosphonate therapy.

Psychological distress 35 years after the Chornobyl accident in the Lithuanian clean-up workers.

The adverse effects on the health of the Chornobyl nuclear power plant accident clean-up workers have been reported previously. However, there is a lack of studies on the mental health of Chornobyl clean-up workers. The current study explored psychological distress in a sample of Lithuanian clean-up workers 35 years after the accident. In total, 107 Lithuanian Chornobyl clean-up workers (Mage = 62.5) and 107 controls were included in the study. The Hospital Anxiety and Depression Scale (HAD) was used for the assessment of anxiety and depression. The depression symptoms were significantly higher in the clean-up workers compared to the control group. The prevalence of severe depression symptoms was 23.4% and 4.7% in the Chornobyl clean-up workers and control groups, respectively. The risk for severe depression was associated with Chornobyl clean-up work (adjusted OR = 5.9). No differences in the anxiety symptoms were found between clean-up workers and controls. The study revealed the deteriorated mental health of the Lithuanian Chornobyl clean-up workers 35 years after the disaster - in particular, high levels of depression. Psychosocial support programmes for clean-up workers should be provided to mitigate the adverse effects of the disaster.

Inherited and De Novo Variation in Lithuanian Genomes: Introduction to the Analysis of the Generational Shift.

Most genetic variants are rare and specific to the population, highlighting the importance of characterizing local population genetic diversity. Many countries have initiated population-based whole-genome sequencing (WGS) studies. Genomic variation within Lithuanian families are not available in the public databases. Here, we describe initial findings of a high-coverage (an average of 36.27×) whole genome sequencing for 25 trios of the Lithuanian population. Each genome on average carried approximately 4,701,473 (±28,255) variants, where 80.6% (3,787,626) were single nucleotide polymorphisms (SNPs), and the rest 19.4% were indels. An average of 12.45% was novel according to dbSNP (build 150). The WGS structural variation (SV) analysis identified on average 9133 (±85.10) SVs, of which 95.85% were novel. De novo single nucleotide variation (SNV) analysis identified 4417 variants, where 1.1% de novo SNVs were exonic, 43.9% intronic, 51.9% intergenic, and the rest 3.13% in UTR or downstream sequence. Three potential pathogenic de novo variants in the ZSWIM8, CDC42EP1, and RELA genes were identified. Our findings provide useful information on local human population genomic variation, especially for de novo variants, and will be a valuable resource for further genetic studies, and medical implications.

Variation in FGF1, FOXE1, and TIMP2 genes is associated with nonsyndromic cleft lip with or without cleft palate.

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common complex birth defect caused by the interaction between multiple genes and environmental factors. METHODS: Five hundred and eighty-seven single nucleotide polymorphisms in 40 candidate genes related to orofacial clefting were tested for association with CL/P in a clefting sample composed of 300 patients and 606 controls from Estonian, Latvian, and Lithuanian populations. RESULTS: In case-control comparisons, the minor alleles of FGF1 rs34010 (p = 4.56 × 10(-4) ), WNT9B rs4968282 (p = 0.0013), and FOXE1 rs7860144 (p = 0.0021) were associated with a decreased risk of CL/P. Multiple haplotypes in FGF1, FOXE1, and TIMP2 and haplotypes in WNT9B, PVRL2, and LHX8 were associated with CL/P. The strongest association was found for protective haplotype rs250092/rs34010 GT in the FGF1 gene (p = 5.01 × 10(-4) ). The strongest epistatic interaction was observed between the COL2A1 and WNT3 genes. CONCLUSIONS: Our results provide for the first time evidence implicating FGF1 in the occurrence of CL/P, and support TIMP2 and WNT9B as novel loci predisposing to CL/P. We have also replicated recently reported significant associations between variants in or near FOXE1 and CL/P. It is likely that variation in FOXE1, TIMP2, and the FGF and Wnt signaling pathway genes confers susceptibility to nonsyndromic CL/P in Northeastern European populations.

Significant Association Between Huntingtin Gene Mutation and Prevalence of Hopelessness, Depression and Anxiety Symptoms.

SUMMARY BACKGROUND: In Huntington's disease psychiatric symptoms may manifest prior to motor dysfunction. Such symptoms negatively impact people's quality of life and can worsen the course of the primary disease. The aim of the present study was to assess and compare depression, anxiety and hopelessness rates in individuals with and without an abnormal expansion of CAG repeats in the huntingtin (HTT) gene and healthy controls. MATERIALS AND METHODS: Study involved 31 individuals referred for genetic testing for Huntington's disease and a control group of 41. Depressive and anxiety symptoms were assessed using Beck Hopelessness Scale (BHS) and Hospital Anxiety and Depression Scale (HADS). Results between groups were compared using the Mann-Whitney U test. Two-sided Bonferroni corrected p-value was set at ≤0.017. RESULTS: Individuals with HTT gene mutation ("gene mutation positive", GMP) (N=20) scored higher on the HADS depression subscale (5.90 ± 4.52 vs 1.36 ± 1.91; p ≤ 0.017) than those without HTT gene mutation ("gene mutation negative", GMN) (N=11). GMP and control groups scored higher than the GMN group on the BHS (5.65 ± 3.91 vs 2.09 ± 1.64 and 5.27 ± 4.11 vs 2.09 ± 1.64, respectively; p ≤ 0.017). No differences in anxiety levels were found. CONCLUSIONS: Depressive symptoms and hopelessness were more prevalent in individuals with HTT gene mutation than in individuals who were tested but had no said mutation. Such results emphasise the importance of timely diagnosis and treatment of psychiatric comorbidities in individuals affected by Huntington's disease.

Possible Protective Effect of LOXL1 Variant in the Cohort of Chernobyl Catastrophe Clean-Up Workers.

Ionising radiation (IR) is an environmental factor known to alter genomes and therefore challenge organisms to adapt. Lithuanian clean-up workers of the Chernobyl nuclear disaster (LCWC) experienced high doses of IR, leading to different consequences. This study aims to characterise a unique protective genomic variation in a relatively healthy LCWC group. This variation influenced their individual reaction to IR and potentially protects against certain diseases such as exfoliation syndrome and glaucoma. Clinical and IR dosage data were collected using a questionnaire to characterise the cohort of 93 LCWC. Genome-wide genotyping using Illumina beadchip technology was performed. The control group included 466 unrelated, self-reported healthy individuals of Lithuanian descent. Genotypes were filtered out from the microarray dataset using a catalogue of SNPs. The data were used to perform association, linkage disequilibrium, and epistasis analysis. Phenotype data analysis showed the distribution of the most common disease groups among the LCWC. A genomic variant of statistical significance (Fishers' exact test, p = 0.019), rs3825942, was identified in LOXL1 (NM_005576.4:c.458G>A). Linkage disequilibrium and epistasis analysis for this variant identified the genes LHFPL3, GALNT6, PIH1D1, ANKS1B, and METRNL as potentially involved in the etiopathogenesis of exfoliation syndrome and glaucoma, which were not previously associated with the disease. The LOXL1 variant is mostly considered a risk factor in the development of exfoliation syndrome and glaucoma. The influence of recent positive selection, the phenomenon of allele-flipping, and the fact that only individuals with the homozygous reference allele have glaucoma in the cohort of the LCWC suggest otherwise. The identification of rs3825942 and other potentially protective genomic variants may be useful for further analysis of the genetic architecture and etiopathogenetic mechanisms of other multifactorial diseases.

Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes.

Leber Congenital Amaurosis (LCA), the most severe inherited retinal dystrophy, is genetically heterogeneous, with 14 genes accounting for 70% of patients. Here, 91 LCA probands underwent LCA chip analysis and subsequent sequencing of 6 genes (CEP290, CRB1, RPE65, GUCY2D, AIPL1and CRX), revealing mutations in 69% of the cohort, with major involvement of CEP290 (30%). In addition, 11 patients with early-onset retinal dystrophy (EORD) and 13 patients with Senior-Loken syndrome (SLS), LCA-Joubert syndrome (LCA-JS) or cerebello-oculo-renal syndrome (CORS) were included. Exhaustive re-inspection of the overall phenotypes in our LCA cohort revealed novel insights mainly regarding the CEP290-related phenotype. The AHI1 gene was screened as a candidate modifier gene in three patients with the same CEP290 genotype but different neurological involvement. Interestingly, a heterozygous novel AHI1 mutation, p.Asn811Lys, was found in the most severely affected patient. Moreover, AHI1 screening in five other patients with CEP290-related disease and neurological involvement revealed a second novel missense variant, p.His758Pro, in one LCA patient with mild mental retardation and autism. These two AHI1 mutations might thus represent neurological modifiers of CEP290-related disease.

Genetic variants in COL2A1, COL11A2, and IRF6 contribute risk to nonsyndromic cleft palate.

BACKGROUND: Orofacial clefts are among the most common birth defects with a strong genetic component. Nonsyndromic cleft palate (NSCP) is a complex malformation determined by the interaction between multiple genes and environmental risk factors. METHODS: We conducted a case-control association study to investigate the role of 40 candidate genes in predisposition to orofacial clefting. Five hundred ninety-one haplotype tagging single nucleotide polymorphism (tagSNPs) were genotyped in a clefting sample from the Baltic region, composed of 104 patients with nonsyndromic cleft palate and 606 controls from an Estonian, Latvian, and Lithuanian population. RESULTS: In case-control comparisons, the minor alleles of IRF6 rs17389541 (p = 5.45 × 10(-4)) and COL2A1 rs1793949 (p = 7.26 × 10(-4)) were associated with increased risk of NSCP. Multiple haplotypes in COL2A1 and COL11A2 and haplotypes in WNT3, FGFR1, and CLPTM1were associated with NSCP. The strongest associations were found for IRF6 haplotype rs17389541/rs9430018 GT (p = 2.23 × 10(-4)) and COL2A1 haplotype rs12822608/rs6823 GC (p = 3.68 × 10(-4)). The strongest epistatic interactions were observed between MSX1 and BMP2, FGF1 and PVRL2, and COL2A1 and FGF2 genes. CONCLUSIONS: This study provides for the first time evidence of the implication of IRF6, COL2A1, and WNT3 in the occurrence of NSCP. It is likely that variation in cartilage collagen II and XI genes, IRF6, and the Wnt and FGF signaling pathway genes contributes susceptibility to nonsyndromic cleft palate in Northeastern European populations.

Juvenile Huntington's disease: two case reports and a review of the literature.

BACKGROUND: Huntington's disease is a rare, autosomal dominant neurodegenerative disease characterized by motor, cognitive, and psychiatric symptoms. Usually, the disease symptoms first appear around the age of 40, but in 5-10% of cases, they manifest before the age of 21. This is then referred to as juvenile Huntington's disease. According to the small number of cases reported in the literature, the course of juvenile Huntington's disease significantly differs from adult onset and shows significant interpatient variability, making every case unique. CASE PRESENTATION: Our study aims to highlight the complexity and diversity of rare juvenile Huntington's disease. We report cases of two Caucasian patients with chronic tics referred to the Huntington's Disease Competence Center of Vilnius University Hospital Santaros Klinikos with suspicion of juvenile Huntington's disease due to the appearance of chronic motor tics, and behavior problems. The diagnosis of juvenile Huntington's disease was confirmed on both clinical and genetic grounds. In both cases described, the patients developed symptoms in all three main groups: motor, cognitive, and psychiatric. However, the first patient was experiencing more severe psychiatric symptoms; in the second case, motor symptoms (rigidity, tremor) were more prominent. In both cases, apathy was one of the first symptoms and affected patients' motivation to participate in treatment actively. These two case descriptions serve as an important message for clinicians seeing patients with chronic tics and gradually worsening mood and behavior, indicating the need to investigate them for rare genetic disorders. CONCLUSIONS: Description of these two clinical cases of juvenile Huntington's disease provides insight into how differently it manifests and progresses in young patients and the difficulties the patients and their families face. There were different but painful ways for families to accept the diagnosis. Because the disease inevitably affects the patient's closest ones, it is crucial to also provide adequate psychological and social support to all the family members. Establishment of multidisciplinary specialist centers for Huntington's disease, as demonstrated by our experience, not only allows timely diagnosis and treatment plans but also ensures thorough disease management and care for patients and systematic support for their families.

HMGA2 Variants in Silver-Russell Syndrome: Homozygous and Heterozygous Occurrence.

CONTEXT: Silver-Russell syndrome (SRS) is a clinical and molecular heterogeneous disorder associated with short stature, typical facial gestalt, and body asymmetry. Though molecular causes of SRS can be identified in a significant number of patients, about one-half of patients currently remain without a molecular diagnosis. However, determination of the molecular cause is required for a targeted treatment and genetic counselling. OBJECTIVE: The aim of this study was to corroborate the role of HMGA2 as an SRS-causing gene and reevaluate its mode of inheritance. DESIGN, SETTING, PATIENTS: Patients were part of an ongoing study aiming on SRS-causing genes. They were classified according to the Netchine-Harbison clinical scoring system, and DNA samples were investigated by whole exome sequencing. Common molecular causes of SRS were excluded before. RESULTS: Three novel pathogenic HMGA2 variants were identified in 5 patients from 3 SRS families, and fulfilling diagnostic criteria of SRS. For the first time, homozygosity for a variant in HMGA2 could be identified in a severely affected sibpair, whereas parents carrying heterozygous variants had a mild phenotype. Treatment with recombinant growth hormone led to a catch-up growth in 1 patient, whereas all others did not receive growth hormone and stayed small. One patient developed type 2 diabetes at age 30 years. CONCLUSIONS: Identification of novel pathogenic variants confirms HMGA2 as an SRS-causing gene; thus, HMGA2 testing should be implemented in molecular SRS diagnostic workup. Furthermore, inheritance of HMGA2 is variable depending on the severity of the variant and its consequence for protein function.

Opposite chromosome constitutions due to a familial translocation t(1;21)(q43;q22) in 2 cousins with development delay and congenital anomalies: A case report.

RATIONALE: Chromosomal rearrangements are the major cause of multiple congenital abnormalities and intellectual disability. PATIENT CONCERNS AND DIAGNOSIS: We report 2 first cousins with unbalanced chromosomal aberrations of chromosomes 1 and 21, resulting from balanced familial translocation. Chromosome microarray analysis revealed 8.5 Mb1q43q44 duplication/21q22.2q22.3 deletion and 6.8 Mb 1q43q44 deletion/21q22.2q22.3 duplication. Among other features, cognitive and motor development delay and craniofacial anomalies are present in both patients, whereas congenital heart defect and hearing impairment is only present in patient carrying 1q43q44 duplication/21q22.2q22.3 deletion. LESSONS: In this report, we provide detailed analysis of the phenotypic features of both patients as well as compare our data with previously published reports of similar aberrations and discuss possible functional effects of AKT3, CEP170, ZBTB18, DSCAM, and TMPRSS3 genes included in the deleted and/or duplicated regions. Partial trisomy 1q/monosomy 21q has only been reported once before, and this is the first report of partial monosomy 1q/trisomy 21q. The expressed phenotype of mirroring chromosomal aberrations in our patients supports the previous suggestion that the dosage effect of some of the genes included in deleted/duplicated regions may result in opposite phenotypes of the patients.