In all domains studied, adverse conditions were more prevalent among VLGA infants than among the FT control group. Efforts to reduce neonatal morbidity in preterm infants should be a key priority for health care in Estonia.

PMM2-CDG (MIM#212065) is the most common type of congenital disorders of glycosylation (CDG) caused by mutations in PMM2 (MIM#601785). In Estonia, five patients from three families have been diagnosed with PMM2-CDG. Our aim was to evaluate the presence of different PMM2-CDG-causing mutations in a population-based cohort and to calculate the expected frequency of PMM2-CDG in Estonia. Also, we analyzed the prevalence of PMM2-CDG based on our patient group data. To calculate the expected frequency of PMM2-CDG, we used the whole genome sequencing data of 2,244 participants from biobank of the Estonian Genome Center, University of Tartu. Nineteen individuals carried mutated PMM2 alleles and altogether, five different mutations were identified. The observed carrier frequency for all PMM2 disease-causing mutations was thus 1/118, and for the most frequent mutation p.R141H, 1/224. The expected frequency of the disease in Estonian population is 1/77,000. It is comparable to the current prevalence of PMM2-CDG for the less than 18 years age group, which is 1/79,000. In conclusion, the frequency of PMM2-CDG in Estonia is lower than in other European populations reported thus far. We demonstrate that biobank data can be useful for gaining new information about the epidemiology of the PMM2-CDG.

Vitamin B12 deficiency seems to be more common worldwide than previously thought. However, only a few reports based on data from newborn screening (NBS) programs have drawn attention to that subject. In Estonia, over the past three years, we have diagnosed 14 newborns with congenital acquired vitamin B12 deficiency. Therefore, the incidence of that condition is 33.8/100,000 live births, which is considerably more than previously believed. None of the newborns had any clinical symptoms associated with vitamin B12 deficiency before the treatment, and all biochemical markers normalized after treatment, which strongly supports the presence of treatable congenital deficiency of vitamin B12. During the screening period, we began using actively ratios of some metabolites like propionylcarnitine (C3) to acetylcarnitine (C2) and C3 to palmitoylcarnitine (C16) to improve the identification of newborns with acquired vitamin B12 deficiency.In the light of the results obtained, we will continue to screen the congenital acquired vitamin B12 deficiency among our NBS program. Every child with aberrant C3, C3/C2 and C3/C16 will be thoroughly examined to exclude acquired vitamin B12 deficiency, which can easily be corrected in most cases.

Imprinting disorders (ImpDis) represent a small group of rare congenital diseases primarily affecting growth, development, and the hormonal and metabolic systems. The aim of present study was to identify the prevalence of the ImpDis in Estonia, to describe trends in the live birth prevalence of these disorders between 1998 and 2016, and to compare the results with previously published data. We retrospectively reviewed the records of all Estonian patients since 1998 with both molecularly and clinically diagnosed ImpDis. A prospective study was also conducted, in which all patients with clinical suspicion for an ImpDis were molecularly analyzed. Eighty-seven individuals with ImpDis were identified. Twenty-seven (31%) of them had Prader-Willi syndrome (PWS), 15 (17%) had Angelman syndrome (AS), 15 (17%) had Silver-Russell syndrome (SRS), 12 (14%) had Beckwith-Wiedemann syndrome (BWS), 10 (11%) had pseudo-or pseudopseudohypoparathyroidism, four had central precocious puberty, two had Temple syndrome, one had transient neonatal diabetes mellitus, and one had myoclonusdystonia syndrome. One third of SRS and BWS cases fulfilled the diagnostic criteria for these disorders, but tested negative for genetic abnormalities. Seventy-six individuals were alive as of

along with other distinctive characteristics like asymmetry of body and limbs, craniofacial features, and 5th finger (F5) clinodactyly. Beckwith-Wiedemann syndrome (BWS, OMIM: 130650) is also a growth-affecting disorder which causes overgrowth with many additional clinical features like macroglossia, organomegaly, and increased risk of childhood tumors [Weksberg et al., 2010]. The most common molecular cause for both syndromes is an abnormal regulation of genes in chromosomal region 11p15 [Gicquel et al., 2005], where 2 imprinting control regions (ICR1 and ICR2) control fetal and postnatal growth. ICR1 contains the maternally expressed H19 gene and the paternally expressed IGF2 gene, whereas ICR2 contains the maternally expressed KCNQ1 and CDKN1C genes and the paternally expressed KCNQ1OT1 gene. Normally, genes that are expressed in 1 allele are imprinted (methylated) and silenced in the other allele. Imprinting disturbances lead to abnormal expression of these genes and the clinical phenotypes of SRS or BWS. Approximately 40% of SRS patients show hypomethylation of ICR1, whereas up to 50% of BWS patients have ICR2 hypomethylation [Eggermann et al., 2008]. In addition, in SRS and BWS patients, numerous submicroscopic chromosomal disturbances have been described, among them duplications, deletions, inversions and/or translocations affecting chromosome 11p15 [Begemann et al., 2012;Fokstuen and Kotzot, 2014]. Large duplicaKey Words 11p15 duplication · 11p15 imprinting disorders · Beckwith-Wiedemann syndrome · Imprinting control region 1 · Imprinting control region 2 · Silver-Russell syndrome Abstract Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) are 2 opposite growth-affecting disorders. The common molecular cause for both syndromes is an abnormal regulation of genes in chromosomal region 11p15, where 2 imprinting control regions (ICR) control fetal and postnatal growth. Also, many submicroscopic chromosomal disturbances like duplications in 11p15 have been described among SRS and BWS patients. Duplications involving both ICRs cause SRS or BWS, depending on which parent the aberration is inherited from. We describe to our knowledge the smallest familial pure 1.3-Mb duplication in chromosomal region 11p15.5p15.4 that involves both ICRs and is present in 3 generations causing an SRS or BWS phenotype.

No abstract

The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein syntaxin-5 (Stx5) is essential for Golgi transport. In humans, the STX5 mRNA encodes two protein isoforms, Stx5 Long (Stx5L) from the first starting methionine and Stx5 Short (Stx5S) from an alternative starting methionine at position 55. In this study, we identify a human disorder caused by a single missense substitution in the second starting methionine (p.M55V), resulting in complete loss of the short isoform. Patients suffer from an early fatal multisystem disease, including severe liver disease, skeletal abnormalities and abnormal glycosylation. Primary human dermal fibroblasts isolated from these patients show defective glycosylation, altered Golgi morphology as measured by electron microscopy, mislocalization of glycosyltransferases, and compromised ER-Golgi trafficking. Measurements of cognate binding SNAREs, based on biotin-synchronizable forms of Stx5 (the RUSH system) and Förster resonance energy transfer (FRET), revealed that the short isoform of Stx5 is essential for intra-Golgi transport. Alternative starting codons of Stx5 are thus linked to human disease, demonstrating that the site of translation initiation is an important new layer of regulating protein trafficking.

Congenital disorders of glycosylation (CDG) are a widely acknowledged group of metabolic diseases. PMM2-CDG is the most frequently diagnosed CDG with a prevalence as high as one in 20,000. In contrast, the prevalence of other CDG types remains unknown. This study aimed to analyze the estimated prevalence of different N-linked protein glycosylation disorders. We extracted allele frequencies for diverse populations from The Genome Aggregation Database (gnomAD), encompassing variant frequency information from 141,456 individuals. To identify pathogenic variants, we used the ClinVar database as a primary source. High confidence loss-of-function variants as defined by the LOFTEE algorithm were also classified as pathogenic. After summing up population frequencies for pathogenic alleles, estimated disease birth prevalence values with confidence intervals were calculated using the Bayesian method. We first validated our approach using two more common recessive disorders (cystic fibrosis and phenylketonuria) by showing that the estimated prevalences calculated from population allele frequencies were in accordance with previously published epidemiological studies. Among assessed 27 autosomal recessive N-glycosylation disorders, the only disease with estimated birth prevalence higher than one in 100,000 was PMM2-CDG (in both, all gnomAD individuals and those with European ancestry). The combined prevalence of 27 different N-glycosylation disorders was around one in 22,000 Europeans but varied considerably across populations. We will show estimated prevalence data from diverse populations and explain the possible pitfalls of this analysis. Still, we are confident that these data will guide CDG research and clinical care to identify CDG across populations.