Interstitial 1p36 Deletion Syndrome Encompassing CAMTA1 Gene: A Case Report

Nydia Rena Benita Sihombing ¹, Nani Maharani ¹, Agustini Utari ^1,2, Tri Indah Winarni ^1,*

1. Center for Biomedical Research (CEBIOR), Faculty of Medicine, Universitas Diponegoro, Jalan Prof. Mr. Sunario, Semarang 50275, Indonesia

2. Department of Pediatrics, Faculty of Medicine, Universitas Diponegoro, Jalan Prof. Mr. Sunario, Semarang 50275, Indonesia

* Correspondence: Tri Indah Winarni

Academic Editor: Ying S. Zou

Collection: Genetic Testing

Received: November 29, 2024 | Accepted: January 26, 2025 | Published: February 05, 2025

OBM Genetics 2025, Volume 9, Issue 1, doi:10.21926/obm.genet.2501284

Recommended citation: Sihombing NRB, Maharani N, Utari A, Winarni TI. Interstitial 1p36 Deletion Syndrome Encompassing CAMTA1 Gene: A Case Report. OBM Genetics 2025; 9(1): 284; doi:10.21926/obm.genet.2501284.

© 2025 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

1. Introduction

Chromosome 1p36 deletion is one of the most common terminal deletion syndromes, affecting approximately 1 in 5,000 live births [1]. While pure terminal deletions have been reported in the majority of cases, interstitial deletions are less commonly found in roughly 30% of cases, and the remaining 10% of cases were derivative chromosomes and complex rearrangements [2,3]. Clinical features of the syndrome vary from developmental delay, intellectual disability, cardiovascular abnormalities, seizures, and vision problems [4].

The majority of cases of 1p36 deletion syndrome are not inherited; there is no history of disorders in the family members. The deletion occurs as a random event/de novo due to crossing-over errors in the first meiotic division (eggs or sperm) or in early fetal development for mosaic cases [5]. Determination of the parental origin has been reported that 60% of de novo 1p36 terminal deletions are derived from maternally inherited chromosomes [6,7]. Besides distinctive facial features (straight eyebrows, deeply set eyes, midface retrusion, wide and depressed nasal bridge, long philtrum, pointed chin, large and late-closing anterior fontanel, micro brachycephaly, epicanthal folds, and low-set, posteriorly rotated, abnormal ears), individuals with 1p36 deletion have global developmental delay and intellectual disabilities [8]. Phenotype variability, but not the severity, is associated with the heterozygous size of deletion and various genes involvement, critical region for the various phenotype have been delineated and reported including MMP23B, GABRD, SKI, PRDM16, KCNAB2, RERE, UBE4B, CASZ1, PDPN, SPEN, ECE1, HSPG2, and LUZP1 strongly implicated in 1p36 deletion syndrome phenotype [1,2].

So far, the involvement of the calmodulin-binding transcription activator 1 (CAMTA1) gene in 1p36 deletion syndrome is less explored. Deep phenotyping in 1p36 deletion syndrome reported one out of 15 participants with deletion of 400 kb involving CAMTA 1 gene having mild intellectual disabilities and gait ataxia [9]. The phenotype spectrum in CAMTA1 pathogenic variants includes developmental delay, cerebellar dysfunction, and behavioral abnormalities [10]. We present an individual with developmental delay, congenital heart defect, and interstitial 1p36 deletion syndrome, encompassing deleted CAMTA1 gene region.

2. Case Report

A one-year-old male baby came with difficulty feeding, bronchopneumonia, and developmental delay. He has had feeding problems in the last month. The patient is the first child of the family, with both parents aged 25 years. He was born prematurely at 36 weeks with asphyxia and a low birth weight of 1.5 kilograms. The mother had a history of oligohydramnios. The parents recalled no exposure to mutagenic agents. At 2.5 months old (corrected age 1.5 months), he had severe short stature (Height for Age Z score (HAZ): -5.14 SD), underweight (Weight for Age Z score (WAZ): -4.96 SD), and microcephaly (Head Circumference Z score (HCZ): -5.13 SD). On examination, his weight was 3,795 grams (WAZ: -7.03 SD), length 63 cm (HAZ: -6.01 SD), and head circumference of 37 cm (HCZ: -7.34 SD). The patient had facial dysmorphic features such as microphthalmia, entropion, down-slanting palpebral fissures, malformed and low-set ears, and bulbous nose tip, as seen in Figure 1. He also had mature retinal vessels and nasolacrimal duct obstruction. On extremities, he had congenital talipes equinovarus, clinodactyly, and a single palmar crease on his right hand. Genital examination showed glandular hypospadias. Echocardiography showed atrial septal defect, with spontaneous closure at age 1.5 years.

Figure 1 Frontal facial picture of the patient showed dysmorphology of the face, i.e., down-slanting palpebral fissures, strabismus, telecanthus, and bulbous nose tip.

At the last follow-up, he was 1 year and 8 months old. His parents were concerned about self-injurious behavior, and he could not sit alone. He was able to say words without meaning. On physical examination, strabismus and nystagmus were observed. The parents refused to do an MRI examination. Renal sonography showed no abnormality. Routine cytogenetic analysis revealed 46,XY karyotype, with no abnormality seen. Upon chromosomal microarray examination using Human CytoSNP-12 v2.1 Bead-Chip kit chromosomal microarray for NextSeq (Illumina) comprising 301,232 markers, the result showed an abnormal male with a loss of 257.2 kb in chromosome 1p36.31 (arr[GRCh37/hg19] 1p36.31(6,778,583-7,035,830)×1). The only known gene involved in the deletion of chromosome 1p36 was CAMTA1, as shown in Figure 2. Another reported CNV was a 206.5 kb loss in chromosome 2q37.1 (arr[GRCh37/hg19] 2q37.1(235,369,660-235,576,220)×1). The deletion encompassed ADP ribosylation factor-like GTPase 4C (ARL4C) gene. This gene was not categorized as a disease-causing gene on the OMIM database [11]. A written informed consent for examination, genetic analysis, and publication has been obtained from the patient’s parents.

Figure 2 UCSC Genome Browser overview of our case, compared to two other cases involving CAMTA1 gene [12,13].

3. Discussion

To our knowledge, we described the first case of 1p36 interstitial microdeletion syndrome in Indonesia, which involved only the CAMTA1 gene. Interstitial deletion encompasses 10-29% of all 1p36 deletion syndrome cases. Meanwhile, known deletion sizes are highly variable, from as small as 49 Kb up to more than 16 Mb [13,14]. Some clinical features have been delineated and mapped into critical regions, such as intellectual disability/developmental delay, epilepsy, microcephaly, cardiovascular malformations, and limb abnormalities [3,9]. The behavioral disorder is one of the characteristics seen in 1p36 deletion patients. Jacquin et al. found that 75% of the individuals with 1p36 deletion syndrome have behavior abnormalities, including aggressivity, self-injurious behavior, temper tantrums, low frustration tolerance, difficulties in social interaction, and stereotypies [3]. Meanwhile, deep phenotyping in 15 Korean patients with 1p36 deletion syndrome showed four individuals with behavioral characteristics, i.e., ADHD, aggressivity, and Rett-syndrome-like symptoms [9]. Table 1 compares previous studies of 1p36 deletion with our patient. Some clinical features were overlapping; however, no history of seizures, gastrointestinal anomalies, or spinal defects was found in our case.

Table 1 Clinical features of patients with 1p36 deletion.

CAMTA 1 gene located at chromosome 1p36.31 encodes a calcium-responsive transcriptional regulator that is highly expressed in the cerebral cortex and cerebellum and plays a central role in the human central nervous system and has been reported to be involved in several processes, including embryonic development, growth control, sensory mechanisms, and memory [10,16]. Besides, a novel antitumor gene that regulates proliferation and cell cycle in glioma by inhibiting AKT phosphorylation, the alterations in CAMTA1 indicate that defects (expression, mutations, and rearrangements) in the gene alone are not sufficient to drive carcinogenesis [16,17]. The CAMTA1 gene’s first three exons deletion, in our case, involved the CG-1 domain, which is responsible for nuclear localization and transcription regulation on neuronal cells. In previous research by Thevenon et al., the analysis suggested that the haploinsufficiency of CAMTA1 would drive transcriptional misregulation to genes involved with neuronal proliferation and differentiation [13].

Previous studies reported that intragenic CAMTA1 deletions/haploinsufficiency are associated with a spectrum of neurobehavioral phenotypes such as speech problems, developmental delay (DD), learning disabilities, intellectual disabilities (ID), attention deficit hyperactivity disorder (ADHD), irritability, aggressive behavior, movement disorders (gait ataxia, spasticity, motor weakness/low muscle tone, fine motor difficulties), epilepsy, gastrointestinal problems (gastroesophageal reflux, constipation, hernia), eye problems (strabismus, jerky ocular pursuit), and dysmorphic features include broad forehead, deep set eyes, down slanting palpebral fissure, broad nasal tip, long philtrum, small mouth, pointed chin, prominent and posteriorly rotated ears [18,19].

Further MRI and PET scan studies on the patient of Thevenon et al. found several brain abnormalities, including cortical atrophy and hypometabolism of the bilateral superior parietal lobes, precuneus, and cuneus, as well as simplified gyration of gyrus dentatus [20]. Furthermore, CAMTA1 deletion has consequences on the maturation and survival of Purkinje cells of the cerebellum, as observed in the CAMTA1-KO mice with ataxia [21]. These findings suggested that CAMTA1 rearrangement is exclusively involved in giving rise to movement disorder phenotype.

Our patient showed behavioral disorders, i.e., temper tantrums, and when dealing with frustration, he often hit himself on the head or pulled his teeth. Neurobehavioral problems in both 1p36 deletion and CAMTA1 intragenic deletion are commonly found, thus, management of his behavioral disorders should be addressed to avoid escalating problems. Further, overlapping characteristics of patients with other CAMTA1-specific deletions to our case are described in Table 2. All described individuals had brain abnormality from brain imaging, giving a basis to do a CT scan or MRI follow-up in our patient as soon as the parents have consented to.

Table 2 Clinical features of patients with CAMTA1 deletion.

Hypotonia may have contributed to the feeding problems in our patient. Nystagmus was also found to be an early sign of movement abnormalities. Movement disorders and low muscle tone may further complicate an individual’s developmental milestones and growth trajectory if malnutrition is observed. Thus, early physical therapy may improve quality of life, especially to help with feeding problems. Additionally, routine evaluation is warranted to observe movement disorder symptoms, seizures, and behavioral issues, to avoid worsening comorbidities. Meanwhile, the prognosis was primarily influenced by the existence of heart defects and the size of the deletion. Mortality data of 1p36 deletion syndrome was obtained from 8 children, with deletion size ranging from 3.7 to 8.3 Mb [3]. For CAMTA1 rearrangement, most patients reported reaching adulthood [13,19,22]. Another critical aspect is parental counseling. Recent research suggested that more than one-third of the CAMTA1 variants were inherited from an asymptomatic or mildly affected parent, which suggested reduced penetrance and variable expressivity events [23]. Consequently, it is recommended to do parental testing to confirm its inheritance, especially when both parents plan to have another child.

4. Conclusion

This report emphasized a CAMTA1 deletion of 1p36 syndrome, which gives rise to syndromic developmental delay with behavioral problems, cardiac abnormalities, and movement disorders. Most of the patient’s phenotypes were related to the 1p36 deletion syndrome, however, a distinct symptom of movement disorders (i.e., nystagmus) was seen as the basis of CAMTA1 gene involvement, and we suggest adding CAMTA1 as the critical gene of movement disorder phenotype of 1p36 deletion syndrome.

Acknowledgments

We are grateful to the patient and his parents for the cooperation to be included in this report. We thank Dr. Lydia Pratanu from National Women and Children Health Center RSAB Harapan Kita Jakarta, Indonesia for the collaboration in the genetic testing for this patient.

Author Contributions

Nydia Rena Benita Sihombing assisted the physical examination and wrote the initial draft of the case report. Nani Maharani assisted the physical examination and article writing. Agustini Utari was the clinician encountered first with the patient, did the physical examination, genetic counseling, and gave feedback to the case report. Tri Indah Winarni coordinated the study, article writing, and finalized the case report. All authors contributed to revision of the draft and approved the final draft.

Funding

This study was supported by the grant from Universitas Diponegoro, Semarang, Indonesia, with the grant number No:118-02/UN7.6.6/PP/2021.

Competing Interests

The authors have declared that no competing interests exist.