Here we report a further case of “pure” terminal deletion 15q26 associated with complex CHD. Fifteen other cases with such aberration and CHD were previously described. Table 1 summarizes clinical and cytogenetic data in these patients and ours.
Our proband share many relevant symptoms with others especially pre and post natal growth retardation, developmental delay, skeletal anomalies, microcephaly, micrognathia and ear anomaly. In addition eye anomalies were observed less frequently. Less common features were found in some cases including kidney anomaly, CDH and lung hypoplasia; however this was lacking in our patient. Through this table, we also note that the CHD was most often complex with several concomitant abnormalities and so was our patient. among the major cardiac defect are ASD/VSD and aortic arch anomaly. Valvulopathy, patent ductus arteriosus, cardiac shunt and hypoplastic heart were irregularly described. Our patient shared some of this anomalies namely ASD and cardiac shunt, however she lacked VSD, AAA and valvular defect. Cardiomegaly was an unusual feature reported exclusively in our patient.
Array analysis allowed us to characterize a de novo 9.15 Mb deletion within the 15q26.1q26.3 region. Comparable aberrations are often reported as de novo. Most often, terminal 15q deletions are found in combination with a terminal duplication of another chromosome due to an unbalanced translocation. To the best of our knowledge and according to the DECIPHER database, a deletion of this specific size has not been reported previously. Based on the Genome Data viewer (https://www.ncbi.nlm.nih.gov/genome/gdv/ ), the deleted segment encompasse thirty six HGNC genes, nineteen of theme are referenced in the OMIM database, among which only IGF1R, MCTP2, NR2F2, CHD2 and MEF2A are consistant with the phenotype described in our proband: (Figure. 3)
NR2F2 (Nuclear NR2F2 (Nuclear Receptor Subfamily 2, Group F, Member 2) (MIM 107773), located at 15q26.2 locus, is involved in angiogenesis and heart development (10), thereby contributing in signalization between the endothelial and mesenchymal area. Indeed, NR2F2 haploinsufficiency in patients with a 15q26 deletion appears to be associated with heart malformations (11). In addition, variants within the NR2F2 gene were found to cause non-syndromic atrioventricular septal defects (AVSDs) and other heart defects as well (12) . Moreover, this gene has been implicated to be involved in some patients with diaphragmatic hernia (6, 13), but this was not reported in others (14, 15) nor present in our patient.
MEF2A (Mads Box Transcription Enhancer Factor 2, Polypeptide A) (MIM 600660), mapped to the human chromosome 15q26.3 region, is member of the myocyte enhancer family of transcription factors (MEF2); a family of four strictly related transcriptions factors (MEF2A to MEF2D) (16). Protein products of these factors are involved in development, morphogenesis and myogenesis of skeletal, cardiac, and smooth muscle cells (17). The sub unit MEF2A is expressed in endothelial and smooth muscle cells of coronary arteries. Subsequently MEF2A mutations can disturb the growth or differentiation of these cells, increasing the risk of developing coronary artery disease (CAD)/ myocardial infarction (MI)) (18, 19). CAD/MI was not evident in patients with 15q26 deletion involving MEF2A. This could be explained by the relatively young age of these patients compared to others described by Wang and Bhagavatula whose age of diagnosis was between 36 and 80 years (18, 19). Therefore, regular checking up would be useful from the third decade onwards in these patients.
MCTP2 (Multiple C2 Domains-Containing TransmembraneProtein 2) (MIM 616297) is mapped to 15q26.2 and encodes a Multiple C2 domain and transmembrane region protein containing three C2 domains and two transmembrane regions (TMRs) (20). C2 domains play a role in calcium signaling which is mandatory in muscle tissue function (20). Previous studies found that disruption of this gene was associated with congenital left heart obstructive cardiac defects in humans (21); this was observed in two half siblings with coarctation of the aorta (CoA) and a 15q26 deletion encompassing MCTP2 gene (21). A further patient was described with an intragenic duplication of MCTP2 in association with CoA and hypoplastic left heart (21).
IGF1R (insulin like growth factor 1 receptor) (MIM 147370) lies on the 15q26.3 locus. it is bound to the growth factor ligands IGF1 and IGF2 to play a key role in pre- and post-natal development (22). IGF1R also has an important function in the development of the central nervous system (23). The crucial impact of IGF1R on growth processes was underlined by the growth restriction found in individuals with pathogenic variants in the IGF1R gene (3), in addition to patients with a 15q26 deletion leading to haploinsufficiency (24). To the best of our knowledge, no heart anomalies have ever seen in patients carrying IGF1 or IGF1R mutations nor in knockout mice lacking these genes. Therefore, it is unlikely that the onset of CHD is only caused by haploinsufficiency of the IGF1R gene (4).
CHD2 (Chromodaine helicase DNA-binding protein) belongs to a family of ATP-dependant chromatin remodeling proteins known for being important in chromatin regulation (25). Mutations in this gene were associated with severe non-syndromic intellectual Disability (26), as well as epileptic encephalopathy (27). Additionally, disruption of CHD2 was associated with scoliosis in murine models (28). Interestingly, this anomaly was observed in our patient as well as a few in the literature (9, 15, 29). These findings together highlight the involvement of CHD2 dysfunction in neurodevelopmental disorders and scoliosis.
To sum up .This work focused on the main genes whose haploinsufficiency could explain heart disease in patients with 15q26 monosomy, i.e. the NR2F2 and MCTP2 genes involved respectively in AVSDs and AAA/hypoplastic left heart. Scoliosis and mental retardation in our patient would be explained both by the CHD2 gene disruption.
15q26 monosomy should be considered when growth retardation is associated with clinodactyly and/or abnormal toe, heart defect mainly ASD/VSD and/or AAA.