*Contributed equally
Chromosome 3q syndrome is a well-known genetic condition caused by interstitial deletion in the long arm of chromosome 3. The phenotype of this syndrome is variable and the great variability in the extent of these deletions leads to a wide spectrum of clinical manifestations. Terminal 12p deletion represents one of the rarest subtelomeric imbalances; patients with distal monosomy 12p present different phenotypes ranging from muscular hypotonia to autism spectrum disorders. The present study reported a prenatal diagnosis of a male fetus presenting ultrasound evidence of corpus callosum dysplasia and ventriculomegaly showing a 3q13q21.2 deletion and a 12p13.33 microdeletion paternally inherited. Among several features previously attributed to the terminal deletion of 3q, corpus callosum dysplasia and ventriculomegaly have rarely been reported together. As the 12p13.33 microdeletion in the father was associated only with muscular hypotonia and joint laxity, the involvement of terminal 12p deletions in the clinical features of the fetus was not possible to verify during the prenatal period. The present case report may provide a reference for prenatal diagnosis and genetic counseling in patients who present 3q13q21.2 deletions and 12p13.33 microdeletion.
Concomitant presence of two simultaneous genomic losses is a rare event and in most such cases it is difficult to attribute the symptoms to one of the two affected genomic regions. 3q deletion syndrome is a genomic disorder characterized by a great variability of phenotypes associated to the extension of deletion. The clinical features of 3q deletion syndrome range from intellectual disability, motor developmental delay, congenital heart disease, renal and gastrointestinal malformations, autism, congenital hypothyroidism, epilepsy and brain anomalies (
Agenesis or dysplasia of the corpus callosum is a brain malformation with variable clinical expression reported in many syndromes with predominantly genetic etiologies. Dysplasia and dysgenesis of the corpus callosum are nonspecific descriptions that imply defective development of the corpus callosum. The term dysplasia is applied when the morphology of the corpus callosum is altered as a congenital trait. For instance, the corpus callosum may be hump-shaped, kinked, or a striped corpus callosum that lacks an anatomically distinct genu and splenium (
A 35-years-old pregnant woman secundigravida, without a remarkable family history, come in our medical center with a suspicion of a corpus callosum defect after a first ultrasound scan at 22 weeks. Then, we performed a second ultrasound scan confirming the presence of dysplasia of corpus callosum (
Amniotic fluid was collected at 23 weeks of gestation. Measurements of the biparietal diameter and head circumference were obtained from a transverse axial plane of the fetal head. The femur length was measured in a longitudinal scan. Cytogenetic analysis was performed on cultured amniocytes by G-banding according to standard procedures. At last, 16 metaphases were analyzed. Chromosome analysis of parental blood samples was performed using GTG-banding techniques on PHA-stimulated blood lymphocytes. Array comparative genomic hybridization (aCGH) analysis was performed on DNA from cultured amniocytes and DNA from parental blood to characterize the extent of deletion, using 44K platform (Agilent Technologies, Santa Clara, CA) as previously reported (
High ranks of %HI (e.g., 0-10%) indicate that a gene is more likely to exhibit haploinsufficiency, low ranks of %HI (e.g., 90-100%) suggest a gene is less likely to exhibit haploinsufficiency (
The result of fetal karyotype indicated a chromosomal structural anomaly. Specifically, a reduction in length of long arm of one chromosome 3 with an anomalous banding pattern involving bands q13.1 and q21 (
The presented case is unique in harboring two specific deletions in 3q13.13q21.2 and 12p13.33. According to the literature search, there were no reports describing any case with interstitial deletion of the long arm of chromosome 3 and terminal microdeletion of the short arm of chromosome 12. Concomitant presences of two simultaneous genomic losses are rare and in most such cases it is difficult to attribute the symptoms to one of the two affected genomic regions, making genotype-phenotype correlation extremely difficult. Here, we report a prenatal diagnosis of a male fetus presenting ultrasounds evidence of corpus callosum dysplasia and ventriculomegaly showing a 3q13q21 deletion and 12p13.33 microdeletion. Litterature search for 3q13.13q21.2 deletion revealed previously described post natal cases showing several clinical phenotypes including skeletal malformations included scoliosis, lordosis, thoracic kyphosis, joint contractures, and peripheral malformations affecting the hands and feet, corpus callosum malformations, ventriculomegaly, alobar holoprosen-cephaly, skull malformations, autism, attention deficits and epilepsy (
In this case we detected also a terminal 12p deletion reported as one of the rarest subtelomeric imbalance (
Although a phenotype-genotype association to specific genes is not possible, we have speculated a possible association considering the published literature referred to these chromosomal aberrations. Due to the complexity of involved chromosomal imbalances, specific 3q13.13q21.2 deletion might contribute to the corpus callosum and ventriculomegaly, while 12p13.33 deletion could lead to muscular hypotonia, and joint laxity observed in the father of fetus. Remarkably this region contains ERC1 gene appearing as a strong candidate for the aforementioned clinical features, since it was previously reported to be associate with muscle organization (
This case report is expected to provide a reference for clinicians facing with prenatal diagnosis and genetic counseling in pregnant women with diagnosis of 3q13q21.2 deletions or 12p13.33 microdeletion. Clinicians should consider 3q deletion syndrome when they are exploring a diagnosis of fetus with corpus callosum abnormalities or ventriculomegaly and the syndrome should be confirmed by cytogenetic karyotype together with aCHG analysis. Unfortunately, in prenatal period few data are collected regarding neurological development of the fetus and only pediatric neurologists can evaluate neurological features after birth.
An accurate characterization of the fetal chromosomal defects has implications in the couple decision regarding the continuing of the pregnancy or elective abortion and brings important information for the future reproductive options in order to give birth to a healthy baby.
Not applicable.
The datasets generated and/or analyzed during the current study are available in the ArrayExpress repository under the following accession number E-MTAB-12413 deposited at BioStudies platform (
FL, KM, MF were involved in conceptualization and writing the original draft. LSC, RR and FM were involved in experiments. KM and MF performed data analysis. KM, MF and AM confirm the authenticity of all the raw data. AM and CG were involved in design, methodology and correction of the manuscript. All authors have read and approved the final manuscript.
The present study was approved by the local ethical committee of Artemisia SPA (approval no. #2022-0054-001; June 01, 2022). The protocols used in this study adhere to the tenets of the Declaration of Helsinki.
Written informed consent was obtained from subjects involved in the study.
All authors are full-time employees of Artemisia SPA. ALTAMEDICA is a branch of Artemisia SPA involved in Human Genetics and Fetal-Maternal Medical Sciences.
Ultrasound evidence of clinical features of fetus. (A) Red arrows show the corpus callosum dysplasia, which presents as thin. (B) Red arrows show the corpus callosum dysplasia, which is not clearly visible. (C) Axial view of fetal cerebral ventriculomegaly (yellow arrow). (D) Sagittal view of the fetal face shows a flat forehead and facial profile.
G-banded karyotype of fetus and relative ideogram showing the region of chromosome 3 harboring the 3q deletion.
The scatter plot of the array comparative genomic hybridization of the fetus. (A) The deletion at the region 3q13.13q21.2 is estimated to be 12.87 Mb (from 111162064 to 124034052 kb) harboring 81 OMIM genes. (B) The deletion at the region 12p13.33 is estimated to be 1.23 Mb (from 100698 to 1327097 kb) harboring 16 OMIM genes. OMIM, Online Mendelian Inheritance in Man.
Coding genes and graphical representation of 12 chromosome region (12p13.33) involved in microdeletion. The deletion at 12p13.33 detected in our patient is represented by a red box on chromosome. 12p13.33 microdeletion in our patient overlapping pathogenic/likely pathogenic deletions (red bars) in other cases present in the Decipher database (