Abstract
Partial deletion of the long arm of chromosome 1 is a rare chromosomal abnormality that is not associated with congenital heart disease (CHD). Here we report a case of 1q31.1-q32.1 deletion with CHD, bicuspid aortic valve, aortic coarctation, and ventricular septal defect, which were successfully managed with surgeries. Since the phenotypes of partial 1q deletion vary for each patient, careful follow-up is required.
Learning objective
We report a case of 1q31.1-q32.1 deletion with, bicuspid aortic valve, aortic coarctation, and ventricular septal defect, which were successfully managed with surgeries including Yasui procedure.
Keywords: 1q31.1–q32.1 deletion, Congenital heart disease, Yasui procedure
Introduction
Partial deletion of the long arm of chromosome 1 is a rare chromosomal abnormality. Its incidence is thought to be lower than that of the most common terminal deletion in humans, the 1q36 deletion syndrome, which is estimated to occur in 1 in 5000 births. They are typically associated with developmental delay and dysmorphic features. There have been no reports of congenital heart disease (CHD) in patients with 1q deletion.
Here, we report a case of 1q31.1-q32.1 deletion with CHD, bicuspid aortic valve (BAV), coarctation of the aorta (CoA), and ventricular septal defect (VSD).
Case report
The patient's mother was primipara and reported no complications during pregnancy or delivery. The patient was born at 38 weeks of gestation by normal vaginal delivery. His Apgar scores were 7 at 1 min and 10 at 5 min. The birth weight was 1888 g (−3.0 SD), height was 42.5 cm (−2.7 SD), and head circumference was 27.0 cm (−1.6 SD). On date of birth, the patient was hospitalized due to hypoglycemia and cardiac murmur. Facial features were noted, including frontal upsweep of hair, mild palpebral fissure, wide and prominent nasal bridge, thick alar, and thin upper lip (Fig. 1A and B). Chest and abdominal radiography showed deficiency in the bilateral 12th ribs and fused 4th and 5th sacrum. On 1 day of birth, BAV, CoA, and VSD were detected by echocardiography and computed tomography (Fig. 1C). Aortic stenosis (AS) was caused by the BAV with fusion of the left and right leaflets. Narrowing of the aorta was observed from the aortic arch to the isthmus. The VSD was the perimembranous type with a moderate shunt from left to right.
Fig. 1.
Facial appearance and cardiac image.
Facial images of the patient (A, B). Multidetector computed tomography of the heart and great vessels (C). Diffuse hypoplasia of the aortic arch is shown in left panel (arrow head). Ventricular septal defect (VSD) shown in right panel (yellow circle).
PV, pulmonary valve; RV, right ventricle; LV, left ventricle; AV, aortic valve.
The patient underwent bilateral pulmonary artery banding (PAB) 6 days after birth due to pulmonary overcirculation. Extended aortic arch anastomosis, bilateral pulmonary artery debanding, and PAB were performed 2 months after birth. Cardiac catheterization at 9 months of age revealed progression of AS. At 10 months of age, he underwent additional arch repair and Yasui procedure, combining the Norwood procedure and Rastelli procedure.
G-band chromosome analysis of the patient showed deletion of the long arm of chromosome 1. Chromosomal microarray examination revealed heterozygous deletion of 14.6 Mb at 1q31.1-q32.1 (chr1: 187097600–201701850) (Fig. 2).
Fig. 2.
Array-comparative genomic hybridization analysis of chromosome 1 showing a deletion spanning 14.6 Mb in the 1q31.1–q32.1 region.
At 1 year of age, the patient displayed mental and motor retardation with hypotonia and dysphagia, equivalent to the development of a 6-month-old child, whereas the postoperative course was favorable. Presently, he is one and a half years of age and healthy without heart failure.
Discussion
To the best of our knowledge, this is the first case of 1q31.1-q32.1 deletion with CHD. Milani et al. described a case of chromosome 1 deletion of 15.6 Mb at 1q31.1-q32.1, with minor facial anomalies, mild developmental delay, and behavioral disorders [1]. Hyder et al. described a case of 9.55 Mb deletion at 1q31.2-q32.1, with dysmorphic features, intellectual disability, and obesity [2]. In contrast, Mrasek et al. reported a case of 13.9-Mb-sized duplication of 1q31.1–1q32 without phenotypic consequences [3]. Thus, CHD has not been reported, whereas the few cases that were described in the medical literature have a specific phenotype. In our case, the diagnosis was made after external surface or organ malformations were detected in the fetal or neonatal period, while in other cases, the diagnosis was made after growth retardation or developmental delay in early childhood or school age. Microcephaly, micrognathia, and over-plastic ears are commonly reported as phenotypes in cases of 1q long arm deletion. Cases reporting multi-organ malformations including endocrine disorders are also observed, but the phenotype does not always match with the area of the deletion. For example, Maggio et al. reported a case of 1q 25–32 deletion. This case presented with severe growth retardation, facial dysmorphism, multiple organ malformations, and multiple endocrine disorders [4]. On the other hand, a case of deletion 1q 25.3–32.1 reported by Libotte et al. had facial dysmorphism, a borderline neurodegenerative defect similar to Dandy-Walker syndrome and bilateral endopodia, but no multi-organ malformations including CHD [5]. Despite the close proximity of the deletion areas in the above two cases, their phenotypes were different. Although the proximity of the deletion regions in these cases including our case, the phenotypes were different and the age at diagnosis was also different. This may be due to the fact that our patient had CHD, which may have led to early detection of symptoms.
According to the report of the Japanese Society of Pediatric Cardiology and Cardiac Surgery in 2020 [6], the incidence of double outlet right ventricle of VSD type was 1.49 per 10,000 live births and for CoA, 3.13 per 10,000 live births in Japan. Some chromosomal abnormalities have been reported to be associated with aortic morphological abnormalities. 22q11.2 deletion syndrome, trisomy 2q, and trisomy 10p are known to be associated with AS and morphological abnormalities. However, our case did not show a phenotype consistent with those chromosomal abnormalities. Furthermore, apart from the 1q31.1-q32.1 deletion, there were no other deletions or duplications, including the 22q11.2 deletion, and no abnormal chromosome number in our case.
Analysis of the gene content of the deleted region showed the presence of 113 known genes, of which 11 are reported to be Online Mendelian Inheritance in Man disease-associated genes. The majority of genes cause autosomal recessive conditions, such F13B, ASPM, CRB1, PTPRC, and PKP1, whereas CDC73, CACNA1S, and TNNT2 are associated with autosomal dominant conditions (Fig. 2). TNNT2 encodes the tropomyosin-binding subunit of the cardiac troponin complex, is expressed during cardiac development, and has been associated with cardiomyopathies. However, only one case with CoA has been reported in humans [7]. Since CHD is thought to be a multifocal gene disorder, this deletion may not fully explain the pathogenesis of CHD and further comprehensive studies such as whole genome sequencing or RNA sequencing are desired.
Careful surgical planning and follow-up are required for chromosomal deletion syndromes because the phenotypes vary in each patient.
Source of funding
None.
Patient permission/consent statement
The patient's parents were informed and consented to the use of their portrait photograph and to the publication of the paper.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
The authors wish to acknowledge Masaya Aoki, Teruhiko Higashida, Mako Okabe, Hideyuki Naoaka, Keijiro Ibuki, Sayaka Ozawa, Hitoshi Moriuchi, Haruna Hirai, and Eriko Masuda for their expert technical assistance.
References
- 1.Milani D., Bedeschi M.F., Iascone M., Chiarelli G., Cerutti M., Menni F. De novo deletion of 1q31.1-q32.1 in a patient with developmental delay and behavioral disorders. Cytogenet Genome Res. 2012;136:167–170. doi: 10.1159/000336979. [DOI] [PubMed] [Google Scholar]
- 2.Hyder Z., Fairclough A., Douzgou S. Chromosome 1q31.2q32.1 deletion in an adult male with intellectual disability, dysmorphic features and obesity. Clin Dysmorphol. 2019;28:131–136. doi: 10.1097/MCD.0000000000000281. [DOI] [PubMed] [Google Scholar]
- 3.Mrasek K., Kruger G., Bauer I., Muller-Navia J., Liehr T., Weise A. A new unbalanced chromosomal abnormality in 1q31.1 to 1q32 without phenotypic consequences. Cytogenet Genome Res. 2008;121:286–287. doi: 10.1159/000138899. [DOI] [PubMed] [Google Scholar]
- 4.Maggio M.C., Iachininoto R., Arena V., Liotta A. Interstitial deletion of the long arm of chromosome 1 (1q 25–32). Clinical and endocrine features with a long term follow-up. Minerva Pediatr. 2003;55(55–9):59–61. [PubMed] [Google Scholar]
- 5.Libotte F., Bizzoco D., Gabrielli I., Tamburrino C., Ernandez C., Carpineto L., D'Aleo M.P., Cima A., Mesoraca A., Cignini P., Aloisi A., Angioli R., Vitale S.G., Giorlandino C. A new case of interstitial 1q 25.3-32.1 deletion: cytogenetic analysis molecular characterization and ultrasound findings. J Prenat Med. 2015;9:8–11. doi: 10.11138/jpm/2015.9.1.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Japanese Registry of Pediatric Heart Disease (JRPHD) Japanese society of Pediatric Cardilogy and Cardiac Surgery. 2020. https://jspccs.jp/wp-content/uploads/rare_disease_surveillance_2020.pdf
- 7.Caiazza M., Lioncino M., Monda E., Di Fraia F., Verrillo F., Pacileo R., Amodio F., Rubino M., Cirillo A., Fusco A., Romeo E., Scatteia A., Dellegrottaglie S., Calabrò P., Sarubbi B., et al. Troponin T mutation as a cause of left ventricular systolic dysfunction in a young patient with previous surgical correction of aortic coarctation. Biomolecules. 2021;11:696. doi: 10.3390/biom11050696. [DOI] [PMC free article] [PubMed] [Google Scholar]