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Chromosomal microarray analysis (CMA) is now established as the first-tier cytogenetic diagnostic test for fast and accurate detection of chromosomal abnormalities in patients with developmental delay/intellectual disability (DD/ID), multiple congenital anomalies (MCA), and autism spectrum disorders (ASD). We present our experience with using CMA for postnatal and prenatal diagnosis in Estonian patients during 2009–2012. Since 2011, CMA is on the official service list of the Estonian Health Insurance Fund and is performed as the first-tier cytogenetic test for patients with DD/ID, MCA or ASD. A total of 1191 patients were analyzed, including postnatal (1072 [90%] patients and 59 [5%] family members) and prenatal referrals (60 [5%] fetuses). Abnormal results were reported in 298 (25%) patients, with a total of 351 findings (1–3 per individual): 147 (42%) deletions, 106 (30%) duplications, 89 (25%) long contiguous stretches of homozygosity (LCSH) events (>5 Mb), and nine (3%) aneuploidies. Of all findings, 143 (41%) were defined as pathogenic or likely pathogenic; for another 143 findings (41%), most of which were LCSH, the clinical significance remained unknown, while 61 (18%) reported findings can now be reclassified as benign or likely benign. Clinically relevant findings were detected in 126 (11%) patients. However, the proportion of variants of unknown clinical significance was quite high (41% of all findings). It seems that our ability to detect chromosomal abnormalities has far outpaced our ability to understand their role in disease. Thus, the interpretation of CMA findings remains a rather difficult task requiring a close collaboration between clinicians and cytogeneticists.

Klinefelter’s syndrome (KS) is the most common human sex chromosome disorder, with a prevalence of 1 in 660 men. The phenotype is variable, but the most constant findings are small and firm testes, decreased testosterone level, infertility, eunuchoid body proportion, increased height, and learning disabilities, due to the presence of extra X chromosome(s) (Smyth and Bremner 1998). KS patients have frequently other diseases of lung, skin, liver and kidney (Morales et al. 1992; Swerdlow et al. 2005). Restrictive lung defects have been attributed to chest wall abnormalities, decreased respiratory muscle strength and increased chest wall compliance (Huseby and Petersen 1981). The likely cause is, decrease of lung compliance due to diminished elasticity of the lung matrix, but its biochemical cause is unknown (Morales et al. 1992). One of the causes could be the mutations in the alpha-1 antitrypsin (AAT) gene (SERPINE1), which is highly polymorphic, with more than 100 alleles identified so far. The alleles are categorized into normal, deficient and null variants on the basis of the plasma level and function of AAT. The protein phenotype is classified according to the ‘Pi’ (protease inhibitor) system, as defined by plasma isoelectric focusing. Normal Pi M types account for 95% of alleles in Caucasian individuals and are characterized by normal plasma levels. Pi X is a rare normal allele variant. Pi Z, S and null types are the most frequent AAT deficiency variants described in lung pathology, but Pi ZZ is associated with both pulmonary and liver diseases (Kaczor et al. 2007; Greene et al. 2008). AAT gene is located on chromosome 14q32.1 (Schroeder et al. 1985).