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Several studies have suggested that fragile X syndrome (FRAXA), the most common inherited form of mental retardation, originated from a limited number of founder chromosomes. The aim of this study is to assess the genetic origin of fragile X syndrome in a Croatian population. We performed a haplotype analysis of the polymorphic loci DXS548 and FRAXAC1 in 18 unrelated fragile X and 56 control chromosomes. The AGG interspersion pattern of the FMR1 CGG repeat region was analyzed by sequencing. This is the first report on haplotype and AGG interspersion analysis of the fragile X syndrome gene in a Croatian population--the only eastern European population of Slavic origin analyzed so far. Our findings are intriguing, because they show a distinct distribution of the DXS548 and FRAXAC1 alleles in our fragile X population compared to other European fragile X populations. The DXS548/FRAXAC1 haplotype 194/154 (7-3), which is common among normal populations, was found to be the most frequent haplotype in our fragile X population as well. The AGG interspersion analysis indicated that AGG loss rather than haplotype may determine FMRI allele instability. Our results suggest that no common ancestral X chromosome is associated with fragile X syndrome in the Croatian population studied. Further analysis of the origin of fragile X syndrome among other Slavic populations will be necessary to better define its eastern European distribution. KEY WORDS: CGG REPEATS, FRAGILE X SYNDROME, FRAXA, FMR1, DXS548, FRAXAC1, HAPLOTYPE, LINKAGE, MENTAL RETARDATION, CROATIA., Fragile X syndrome (FRAXA, Xg27.3) is the most common inherited form of mental retardation. It is generally caused by an expansion of the CGG repeat region within the FMRI gene. [...]

Acute leukemias are the most common malignant diseases in childhood. The aims of this retrospective cohort study were to investigate the frequency of cytogenetic abnormalities in acute pediatric leukemia; the correlation between cytogenetic abnormalities and 5-year survival; and the correlation between cytogenetic abnormalities and clinical and laboratory features. We included 105 patients; acute lymphoblastic leukemia (ALL) had 80.9% patients, B-cell lineage ALL (B-ALL) 84.7% of them, and T-cell lineage (T-ALL) 15.3%. The overall 5-year survival for B-ALL was 85.9% and for T-ALL was 84.6%. The most common cytogenetic abnormalities in patients with B-ALL were t(12;21)(p13.2;q22.1); ETV6-RUNX1 with 22.2% and hyperdiploidy with 19.4%. Our survival analysis showed that t(12;21)(p13.2;q22.1); ETV6-RUNX1 and t(1;19)(q23;p13.3); TCF3-PBX1 had the best 5-year survival with 100% of patients surviving, whereas t(v;11q23.3); KMT2A rearranged had the worst 5-year survival of just 33.3% of patients surviving after 5 years. We found no difference in 5-year survival in B-ALL when comparing clinical features. Acute myelogenous leukemia had 20 patients with 70.6% 5-year survival. The most common cytogenetic abnormality in acute myelogenous leukemia was t(8;21)(q21;q22.1); RUNX1-RUNX1T1 (20%). In conclusion, this study showed the correlation of different cytogenetic abnormalities with 5-year survival in B-ALL patients. Such correlation was not found when comparing clinical features and 5-year survival of patients with B-ALL. This emphasized the significance of cytogenetic analysis in pediatric leukemia., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Epilepsy is one of the most common neurological disorders with diverse phenotypic characteristics and high genetic heterogeneity. Epilepsy often occurs in childhood, so timely diagnosis and adequate therapy are crucial for preserving quality of life and unhindered development of a child. Next-generation-sequencing (NGS)-based tools have shown potential in increasing diagnostic yield. The primary objective of this study was to evaluate the impact of genetic testing and to investigate the diagnostic utility of targeted gene panel sequencing. This retrospective cohort study included 277 patients aged 6 months to 17 years undergoing NGS with an epilepsy panel covering 142 genes. Of 118 variants detected, 38 (32.2%) were not described in the literature. We identified 64 pathogenic or likely pathogenic variants with an overall diagnostic yield of 23.1%. We showed a significantly higher diagnostic yield in patients with developmental delay (28.9%). Furthermore, we showed that patients with variants reported as pathogenic presented with seizures at a younger age, which led to the conclusion that such children should be included in genomic diagnostic procedures as soon as possible to achieve a correct diagnosis in a timely manner, potentially leading to better treatment and avoidance of unnecessary procedures. Describing and discovering the genetic background of the disease not only leads to a better understanding of the mechanisms of the disorder but also opens the possibility of more precise and individualized treatment based on stratified medicine.

ANK3 encodes multiple isoforms of ankyrin-G, resulting in variegated tissue expression and function, especially regarding its role in neuronal development. Based on the zygosity, location, and type, ANK3 variants result in different neurodevelopmental phenotypes. Autism spectrum disorder has been associated with heterozygous missense variants in ANK3, whereas a more severe neurodevelopmental phenotype is caused by isoform-dependent, autosomal-dominant, or autosomal-recessive loss-of-function variants. Here, we present four individuals affected by a variable neurodevelopmental phenotype harboring a heterozygous frameshift or nonsense variant affecting all ANK3 transcripts. Thus, we provide further evidence of an isoform-based phenotypic continuum underlying ANK3-associated pathologies and expand its phenotypic spectrum., (© 2021. The Author(s).)

ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development.

PurposeIn 2012 we reported in six individuals a clinical condition almost indistinguishable from PLOD1-kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS), caused by biallelic mutations in FKBP14, and characterized by progressive kyphoscoliosis, myopathy, and hearing loss in addition to connective tissue abnormalities such as joint hypermobility and hyperelastic skin. FKBP14 is an ER-resident protein belonging to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases); it catalyzes the folding of type III collagen and interacts with type III, type VI, and type X collagens. Only nine affected individuals have been reported to date.MethodsWe report on a cohort of 17 individuals with FKBP14-kEDS and the follow-up of three previously reported patients, and provide an extensive overview of the disorder and its natural history based on clinical, biochemical, and molecular genetics data.ResultsBased on the frequency of the clinical features of 23 patients from the present and previous cohorts, we define major and minor features of FKBP14-kEDS. We show that myopathy is confirmed by histology and muscle imaging only in some patients, and that hearing impairment is predominantly sensorineural and may not be present in all individuals.ConclusionOur data further support the extensive clinical overlap with PLOD1-kEDS and show that vascular complications are rare manifestations of FKBP14-kEDS.

The sodium leak channel, a Na + -permeable, nonselective cation channel, is widely expressed in the nervous system, contributing a basal Na + -leak conductance and regulating neuronal excitability. A 3-year-old girl, heterozygous for a de novo missense mutation in NALCN (c.956C>T; p.Ala319Val) predicted to be deleterious, presented from birth with: stimulus-induced, episodic contractures of the limbs and face with associated respiratory distress; distal arthrogryposis; severe axial hypotonia; and severe global developmental delay (CLIFAHDD syndrome). In infancy, she manifested a reversed sleep-wake rhythm, nocturnal life-threatening respiratory rhythm disturbances with central apnea. Sevoflurane sensitivity caused respiratory depression and cardiac arrest.

Background: Neonatal hyperbilirubinemia is a common clinical manifestation of the inherited glucose-6-phosphate dehydrogenase (G6PD) deficiency., Aim of the Study: The aim of this study was to investigate the influence of the inherited G6PD deficiency on the appearance of neonatal hyperbilirubinemia in southern Croatia., Methods: The fluorescent spot test (FST) was used in a retrospective study to screen blood samples of 513 male children who had neonatal hyperbilirubinemia, of unknown cause, higher than 240 μmol/L. Fluorescence readings were performed at the beginning and at the fifth and tenth minute of incubation and were classified into three groups bright fluorescence (BF), weak fluorescence (WF) and no fluorescence (NF). Normal samples show bright fluorescence. All NF and WF samples at the fifth minute were quantitatively measured using the spectrophotometric method., Results: Bright fluorescence was present in 461 patients (89.9%) at the fifth minute. The remaining 52 (10.1%) were quantitatively estimated using the spectrophotometric method. G6PD deficiency was observed in 38 patients (7.4%)., Conclusions: Prevalence rate of G6PD deficiency among male newborns with hyperbilirubinemia in southern Croatia is significantly higher (p < 0.01) compared with the previously reported prevalence rate among male in general population of southern Croatia (0.75%). We recommend FST to be performed in hyperbilirubinemic newborns in southern Croatia.

Background: Historically, 50% of spontaneously expelled abortuses have been thought to be chromosomally abnormal; about 60% are trisomies. In general, trisomy 16 is the most frequent chromosomal abnormality, followed by trisomy 21 and trisomy 22. So far only 1 case of a female fetus with multiple congenital malformations associated with full trisomy 5 has been described., Report: We present a case of de novo full trisomy 5 in a spontaneous abortion sample. A young couple with normal constitutional karyotype experienced the second spontaneous abortion at 9 weeks of gestation, with the cytogenetic formula 47,XX,+5 in all analyzed cells., Conclusions: The routine cytogenetic analysis of miscarriages is still an uncommon practice, but it can have a great impact on the management of couples with repeated pregnancy wastage. Besides of the obvious cost benefit for health care, such analysis would help the physician to decide about future patient management, as well as planning the genetic counseling.