Patients with 2q31.1 microdeletion syndrome previously described in the literature had a wide spectrum of signs and symptoms, some of them strongly linked to specific gene haploinsufficiency. From 2006 to 2022, 39 patients (including the proband reported here) with deletions in the range 2q31.1-2q33, diagnosed by the high-resolution CGH microarray technique were found during the screening of cases reported in the literature.[1, 2, 4–14] 64% were female (16/25 cases with gender reported), the median age was 5.25 (IQR: 2-13.8) years; half of the patients (51%, 19/37 cases) had some degree of cognitive impairment (35% were severely impaired);, seizures were present in 35.3% (12/34); absent or abnormal speech in 42.3% (15/35), developmental or growth delay at evaluation in 73% (27/30); abnormal head shape in 64% (23/36), most frequently microcephaly; heart abnormalities in 41.2% (7/17), and 66.7% (24/36) had eye abnormalities including astigmatism, deep-set eyes, downslanting palpebral fissures, strabismus, coloboma, and lacrimal pathology. All patients showed at least one dysmorphic facial feature, including a high or prominent forehead; ear anomalies (mostly low set ears), micrognathia, nasal and tooth abnormalities (crowded, broad and small teeth), or palate abnormalities including cleft, ogival, high or narrow palates.
The median deletion length of the cases was 5.25 Mb (IQR 2.6–11.6 Mb), and several genes are frequently involved, including the HOXD and ZNF clusters, GLS, FRZB, and SATB2 genes (table 1 and Fig. 2). The case presented here is an infant carrying a deletion, above the median (13.12 Mb), in the 2q31-2q32 cytobands who presented with mental retardation, behavior and speech disturbances, seizures, growth delay, and mild facial dysmorphism (Table 1).
Comparing the findings in our patient with those of previously reported cases (see references above, table 1 or Fig. 2), the clinical characteristics delineate the present case as the 2q31.1 microdeletion syndrome. The deletion found is within the genomic segment shared by multiple cases previously reported (Fig. 2), and includes multiple genes such as the FRZB and the HOXD cluster. The latter genes are involved in embryonic development, mainly through cell-to-cell communication, and are linked to the early development of mammalian limbs.[7, 15] In our case, up to 61 genes have been identified that are compromised by the microdeletion found (Fig. 2), and include a cluster of HOXD genes (HOXD13, HOXD11, HXOD10, HOXD9, HXOD8, HOXD4, HOXD3, and HOXD1). The lack of the HOXD cluster was reported in 15 of 38 cases found in the literature review (16/39 with the proband presented here), and all patients who lack HOXD genes presented with limb anomalies (table 1, Fig. 2). Therefore, the camptodactyly and brachydactyly found in our patient probably arose due to the absence of the above-mentioned homeotic genes; these symptoms have been previously reported in other cases with this same condition lacking the HOXD cluster.[2, 4]
The long arm of chromosome 2 has appeared as a candidate region for autism because it contains critical genes for development, and patients with deletions in this location may present manifestations such as the absence of speech and behavior disturbances.[14, 16] Some patients with 2q31 microdeletion syndrome, including the present case, had behavior disturbances; these behaviors include aggression, anxiety, unpredictable mood, hyperactivity, and chaotic movements. One of the deleted genes found in our patient, PRKRA, plays a role in cell response to stress and synaptic plasticity, which is critical for learning and memory;[17] this gene has been shown to be disturbed in 14/38 cases but given that not all patients report behavioral anomalies in the patients, no conclusion or associations can be made. However, other genes that have been linked to behavioral/speech and neurological alterations, particularly in 2q31 deletion syndrome patients are the ZNF804A and the ZNF385B genes, respectively (Fig. 2). Both genes coded zinc-finger proteins that have been associated with mental and neurological abnormalities in this syndrome.[5, 14] However, we found that although several patients with severe cognitive impairment or behavioral disturbance have these genes deleted, including our patient, some others with the same manifestations have no recognizable alterations affecting those genes, suggesting that other factors (e.g. regulatory sequences upstream or downstream of these genes) or loci are contributing to the neurological phenotype seen in patients with 2q31-2q33 microdeletions. In our case, the MRI showed dysgenesis of the corpus callosum, encephalomalacia in the right frontal lobe, retraction of the frontal pole of the lateral ventricle, and periventricular hyperintensities.
Furthermore, the gene TTN, which is also present in the deleted region, is not currently linked to any clinical repercussions in this syndrome, but autosomal dominant cardiomyopathy due to haploinsufficiency of TTN has been reported.[18] Therefore, whether the TTN gene is contributing to the clinical phenotype seen in our patient remains unknown. However, out of the 11 cases with deletions comprising this gene, seven have no information related to heart defects (it is not specified whether the patients did not have symptoms or no evaluation was performed), two do not have cardiac alterations and the remaining two had bicuspid valves, mild hypertension, and atrial and ventricular septal defects. Five patients with no alterations comprising the TTN gene did show heart defects. These results suggest that other genes are involved in cardiovascular manifestations in these patients.
Patients with non-diagnosed 2q31-2q32 microdeletion syndrome presenting the velocardiofacial phenotype, as our patient did, must be given a presumptive diagnosis of the 22q11 microdeletion syndrome, given that this latter condition is one of the most prevalent chromosomic deletions in humans and one of the most frequent syndromes associated with heart congenital diseases.[19] In this manner, a FISH was performed in this case aiming to identify alterations in the 22q11 cytoband, without a positive result; thus, the CGH was performed and the discontinuous deletion in the 2q31-2q32 regions was found, highlighting the importance of techniques with high resolution and DNA coverage to the diagnosis of complex syndromes. Furthermore, given that the use of CGH has allowed a better characterization and definition of the breakpoints of deletions in the DNA, different syndromes are now recognized affecting these regions: the 2q31.1 microdeletion syndrome, 2q31.2q32.3 microdeletion syndrome, and the 2q33.1 microdeletion syndrome.[10] However, our patient had deleted region from all 2q31 cytobands and a large part of the 2q32.1 cytoband, making more complex her phenotype and the determination of what genes are contributing to it when compared to other cases.
In conclusion, we report a patient with a complex, discontinuous heterozygous deletion comprising the 2q31.1 to 2q32.1 region. This is the first patient reported in the literature with a discontinuous deletion affecting these cytobands, making the diagnosis, management, and prognosis of the patient challenging. Furthermore, the literature review, presented in this report, of cases with deletions comprising at least the 2q31.1 cytoband will allow further genotype-phenotype correlations and delineate the clinical symptoms and their frequencies in these patients. Nevertheless, it is important to highlight that differences in deletion length, and therefore, differences in genes deleted can significantly alter the phenotype displayed by each patient. Finally, the CGH technique might help in the diagnosis of complex and rare disorders by allowing the detection of an increasing number of genomic alterations, as well as the identification, with high resolution, of the genes affected in the patients.