IJCS | Volume 33, Nº4, July and August 2020

426 Santos et al. Congenial heart disease and 22q11 deletion Int J Cardiovasc Sci. 2020; 33(4):423-428 Case Report lymphocytes, extracted using the Puregene Blood Core Kit C (Qiagen Sciences Inc., Germantown, MD, USA). The SALSA MLPA probemix P250 DiGeorge syndrome test kit (MRC-Holland BV, Amsterdam, Netherlands) was used to determine the copy number changes in the 22q11.2 region. The MLPAwas performed following the manufacturer’s instructions, and all runs included DNA from three normal controls to calibrate the unknown samples. The reaction products were detected using an ABI-3500 Genetic Analyzer (Applied Biosystems Inc., Foster City, CA, USA). To size the polymerase chain reaction (PCR) products and obtain the peak areas, we used the GeneMapper Software (Applied Biosystems Inc.). These data were exported into the GeneMarker software (Softgenetics LLC, State College, PA, USA) or Coffalyser.Net software (MRC-Holland BV) for analysis. Results The MLPA results of the proband 1’s family showed a deletion of 3Mb extending fromLCR22-A to LCR22-D in the patient, mother, and grandmother. TheMLPA results of the probands 2 and 3’s families showed a deletion of 3 Mb extending from LCR22-A to LCR22-D in the patient andmother. Figure 1 shows the family pedigrees of probands 1, 2, and 3, as well as the MLPA results of these families. Discussion CHDs often occur in association with other malformations and as a feature of well-defined genetic syndromes. Frequently, heart defect is one of the first signs of a genetic disorder that may result in an important medical problem in early childhood. 11 The 22q11 chromosomal region deletion is considered the second most common cause of CHDs after Down syndrome, 12 and cardiovascular manifestations of the 22q11 deletion are highly variable. 13 According to the literature, the del22q11.2 is usually sporadic, with prevalence of familial cases ranging from 6% to 28% of patients with this disorder. 8-10 In the present work, we reported three familial cases of individuals who presented the same 3 Mb deletion in the 22q11 region. Approximately 87% of the patients with 22q11DS have a common 3 Mb deletion region, known as the “common” deleted region (CDR), which includes at least 48 known genes. Smaller deletions may occur more frequently in familial cases than in non-familial cases with del22q11.2. 6 It has been hypothesized that individuals with the small deletion may have a milder phenotype, and a better chance to produce offspring. 13 However, molecular analysis of the 22q11.2 region in our families revealed the presence of 3 Mb deletion in an individual that we had considered as having a mild phenotype. Once familial cases are relatively less frequent, it is difficult to affirm that the size of the deletion is related to familial cases or to the phenotype. The expected 90% frequency of the 3 Mb deletion was observed in the families studied. They presented a clinical variability ranging from the typical characteristics of a 22q11 deletion, as observed in the mother, to only a CHD, as observed in the child. In the present familial reports, we observed that the affected parent was the mother. Devriendt et al., 6 reported that the affected parent of all index patients was also the mother. They concluded that this was compatible with the previous hypothesis that this preference for maternal inheritance in familial cases could be due to either decreased fertility 13,14 or decreased reproductive success 13-15 in the affected males, with respect to the affected females. However, Matsuoka et al., 16 suggested that there was no relationship between fertility and del22q11.2. Although the three families has been investigated to fertility, it is possible that there is a preference for maternal inheritance in familial cases, as pointed out by several authors. 13,14 The role of the 22q11 region genes in nonsyndromic CHDs is unclear. Amutational analysis of the TBX1 gene, whichmaps to the 22q11 chromosomal region commonly deleted in patients with DiGeorge/velocardiofacial syndrome, failed to detect the pathogenetic mutations in nonsyndromic individuals with the specific conotruncal defect subtypes commonly found in del22. 17,18 In the present study, based on the clinical features of the probands, we would not suspect 22q11DS, because the main clinical characteristic was CHD, which was the reason why these children were referred to our clinic. The presence of some of the characteristics of 22q11DS were observed in the mothers (we did not have permission to publish the images of the families), which encouraged us to investigate the presence of the deletion in these individuals. The region in the patients reported here encompasses the TBX1 gene, which can be considered the causative agent, and the differences existing between the mother’s and child’s phenotypes could be attributed to the presence or absence of genes in the breaking points, plus copy number variations in the rest of the genome. 5 Moreover, the possibility that