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Congenital heart disease (CHD) is the most common congenital disorder among live births. When associated with extracardiac abnormalities, it is characterized as a syndromic heart disease (syndromic CHD) and corresponds to 25% of all liveborn infants with a heart defect. The etiology in about 65% of the cases still remains unknown, and in about 35% of the patients, it is associated with genetic factors. In the present study, MLPA and SNP-array techniques were used to investigate a group of 47 patients with syndromic CHD. In total, 16 defects (34%) were identified, of which 12 (25.5%) were classified as pathogenic or probably pathogenic. The most frequent abnormalities were 22q11.2 deletion (22q11.2 deletion syndrome) and 7q11.23 deletion (Williams-Beuren syndrome). We also show that rarer malformations may be associated with syndromic CHD, such as 14q32.33 deletion as well as 17q25.3, 15q11.2 (BP1-BP2), 22q13.31, and 12p13.31 (SLC2A3) duplications. The present study demonstrates that CNVs are important causal factors and should be studied in patients with syndromic CHD. Furthermore, the use of MLPA as a first screening test was appropriate, as this less expensive technology detected 11 of the 12 pathogenic abnormalities (91.6%).

Chromosomal changes are frequently observed in patients with syndromic seizures. Understanding the genetic etiology of this pathology is crucial for the guidance and genetic counseling of families as well as for the establishment of appropriate treatment. A combination of MLPA kits was used to identify pathogenic CNVs in a group of 70 syndromic patients with seizures. Initially, a screening was performed for subtelomeric changes (MLPA P036 and P070 kits) and for the regions most frequently related to microdeletion/microduplication syndromes (MLPA P064). Subsequently, the MLPA P343 was used to identify alterations in the 15q11q13, 16p11.2, and 22q13 regions. Screening with MLPA P343 allowed a 10-15.7% increase in the detection rate of CNVs reinforcing the importance of investigating changes in 15q11q13 and 16p11.2 in syndromic patients with seizures. We also demonstrated that the MLPA technique is an alternative with a great diagnostic potential, and we proposed its use as part of the initial assessment of syndromic patients with seizures.

The clinical manifestations of patients with a 22q11.2 deletion are highly variable and mainly include developmental defects of structures derived from the third and fourth pharyngeal pouches. Laryngeal atresia has occasionally been reported in DiGeorge syndrome as well as in velo-cardio-facial syndrome. We observed three patients with type III laryngeal atresia (glottic web) and 22q11.2 microdeletion. One patient showed a “classical” 22q11.2 deletion phenotype with clinical overlap with DiGeorge and velo-cardio-facial syndromes. However, the pattern of congenital anomalies of the two others was less specific, heart defects and minor anomalies being the only outstanding clinical manifestations suspicious for monosomy 22q11.2. Our findings suggest that laryngeal atresia represents an additional malformation which should prompt investigation of 22q11.2 deletion, especially in combination with congenital heart defects. Am. J. Med. Genet. 70:130–133, 1997. © 1997 Wiley-Liss, Inc.