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Cells from people with Down syndrome (DS) show faster accumulation of DNA damage and epigenetic aging marks. Causative mechanisms remain un-proven and hypotheses range from amplified chromosomal instability to actions of several supernumerary chromosome 21 genes. Plasma immunoglobulin G (IgG) glycosylation profiles are established as a reliable predictor of biological and chronological aging. We performed IgG glycan profiling of n=246 individuals with DS (208 adults and 38 children) from three European populations and compared these to age-, sex- and demography-matched general populations. We uncovered very significantly increased IgG glycosylation aging marks associated with DS. Average levels of IgG glycans without galactose (G0) and those with two galactoses (G2) as a function of age in persons with DS corresponded to levels detected in 19 years older euploid individuals. Some aging marks were significant already in children with DS. Remarkably, the IgG glycan profiles of a child with segmental duplication of only 31 genes on chromosome 21 had values similar to those of age-matched DS children, outside the normal children’s range. This is the first non-epigenetic evidence of accelerated systemic biological aging in DS, suggesting it begins very early in childhood. It points to a causative contribution of the overdose of genes in a short segment of chromosome 21, not previously linked to accelerated aging, opening a route to discovery of hitherto unrecognised mechanisms.

Iako kromosom 17 pokazuje vrlo veliku genetičku nestabilnost, intersticijske delecije unutar regije 17q24 vrlo su rijetke. Bolesnici s ovom promjenom pokazuju heterogen fenotip: mikrocefaliju, tipične dismorfi čne crte, srčane grješke, intelektualno zaostajanje, Andersen-Tawilov sindrom i Carneyev kompleks. Prikazujemo 10-mjesečnu bolesnicu s mikrocefalijom, specifi čnom dismorfi jom te zaostajanjem u tjelesnom i psihomotornom razvoju, kod koje je utvrđena rijetka mikrodelecija regije 17q24.1-q24.3 veličine 5.4 Mb. Ova delecija zahvaća ukupno 30 gena koji kodiraju proteine. Smatramo da su za fenotip bolesnice vjerojatno odgovorni geni PRKCA, PSMD12, KPNA2, PRKAR1A i KCNJ2. Promjene u genu PRKCA pronađene su u osoba s poremećenom kognitivnom funk cijom, dok se haploinsufi cijencija PSMD12 povezuje s neurorazvojnim poremećajima i dismorfi jom. Delecije gena KPNA2, uklju čenog u signalni put sindroma lomljivosti Nijmegen, uzrokuju mikrocefaliju, nizak rast i sindaktiliju. Gen PRKAR1A se povezuje s nastankom Carneyevog kompleksa, a haploinsufi cijencija gena KCNJ2 uzrokuje mišićnu slabost i aritmije. Neki od ovih simptoma nisu zapaženi kod bolesnice, ali bi se, kao i niz drugih komorbiditeta, s vremenom mogli razviti, zbog čega je nužno njeno kontinuirano praćenje., Although chromosome 17 shows high genetic instability, interstitial deletions within 17q24 region are very rare. The phenotype of aff ected patients is heterogeneous but generally includes microcephaly, dysmorphic features, heart defects, intellectual disability, Andersen-Tawil syndrome and Carney complex. We present a 10-month-old proband with rare 5.4 Mb microdeletion of 17q24.1- q24.3 region. Her main clinical manifestations include microcephaly, distinctive dysmorphic features, and hypotrophy. Among 30 deleted protein coding genes, we hypothesize that PRKCA, PSMD12, KPNA2, PRKAR1A, and KCNJ2 might be responsible for the proband’s phenotype. Changes in PRKCA gene have been described in patients with abnormal cognitive function and haploinsuffi - ciency of PSMD12 has been associated with neurodevelopmental disorders and dysmorphia. Deletions of KPNA2 gene, known to be involved in Nijmegen breakage syndrome, are characterized by microcephaly, short stature, and syndactyly. PRKAR1A gene is known to be involved in Carney complex. Haploinsuffi ciency of KCNJ2 gene in this region causes episodes of muscle weakness and arrhythmia. So far, these symptoms have not been observed in the proband. Nevertheless, as these and additional comorbidities might develop over time, continuous monitoring is required.

Aim: To determine the diagnostic yield and criteria that could help to classify and interpret the copy number variations (CNVs) detected by chromosomal microarray (CMA) technique in patients with congenital and developmental abnormalities including dysmorphia, developmental delay (DD) or intellectual disability (ID), autism spectrum disorders (ASD) and congenital anomalies (CA). Method: CMA analysis was performed in 337 patients with DD/ID with or without dysmorphism, ASD, and/or CA. In 30 of 337 patients, chromosomal imbalances had previously been detected by classical cytogenetic and molecular cytogenetic methods. Results: In 73 of 337 patients, clinically relevant variants were detected and better characterized. Most of them were >1 Mb. Variants of unknown clinical significance (VOUS) were discovered in 35 patients. The most common VOUS size category was