Chromosome 4q deletion syndrome: 4q13.3-q21.23 deletion syndrome with mental retardation, congenital heart disease: a case report and literature review

doi:10.21203/rs.3.rs-2631921/v1

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Case Report

Chromosome 4q deletion syndrome: 4q13.3-q21.23 deletion syndrome with mental retardation, congenital heart disease: a case report and literature review

https://doi.org/10.21203/rs.3.rs-2631921/v1

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Objective. Chromosome 4q deletion syndrome is a rare disease, and the reported genotypes cannot fully explain the clinical manifestations. This article aims to present a case that provides ideas for the clinical diagnosis of similar conditions, by adding new genotypes to the 4q deletion fragment gene pool.

Case presentation.A female child aged 7-month and 3-day-old was born after repeated treatments for “cleft palate, atrial septal defect, mixed deafness, corpus callosum developmental malformation” and other diseases. By searching the PubMed, and Web of Science, CNKI, the published literature on chromosome 4 deletion was sorted and analyzed. Whole-genome sequencing,which was diagnosed as 4q13.3-q21.23 deletion syndrome.

Conclusion.The diagnosis of congenital heart defects, progressive growth retardation, and mental retardation with multisystem involvement, and deletion of a gene fragment of chromosome 4 became a disorder to be considered in clinical work. Timely analysis of genetic findings could help confirm the diagnosis.

Chromosome 4q deletion syndrome

Growth retardation

Mental retardation

Literature review

Whole-genome sequencing

Deletion of a gene segment of chromosome 4 leads to a rare congenital disorder that occurs in about 1/100,000 people[1]. The clinical manifestations of patients with chromosome 4 gene deletion syndrome differ due to variations in gene deletion sites. Reportedly, clinical phenotypes are associated with intrauterine growth restriction, growth retardation, hearing impairment, protruding forehead, microcephaly, sparse frontal hair, depressed nasal bridge, small hands and feet, hypotonia, epilepsy, and macular albinism; predicting the prognosis of children is highly difficult [2]. With the rise of high-throughput sequencing technology, more case reports about the deletion of chromosome 4 gene fragments have emerged, and all of them have accurately located the deletion region, making it possible to establish a genotype-phenotype correlation disease map[3, 4]. In this study, whole-exome sequencing technology was used to retrospectively analyze a patient with congenital heart disease, mixed deafness, corpus callosum developmental malformation, growth retardation, and other clinical signs in an outpatient clinic. The patient was diagnosed with 4q13.3-q21.23 gene deletion. In this case report, the clinical case of this syndrome was combined with a review of the relevant literature to improve the understanding of chromosome 4 gene fragment deletion.

The patient is a 7-month and 3-day-old Chinese female child. Who was repeatedly treated, owing to "pneumonia, pediatric enteritis, cleft palate, congenital heart disease (atrial septal defect), mixed deafness, corpus callosum developmental malformation, and possible hydrocephalus". In the 40th week of gestation, the patient was born with a weight of 2980g, and a length of 48cm, without respiratory complications and was breastfed after birth. The patient is the second child of non-consanguineous healthy parents, the first child is healthy. Informed consent was obtained from the parents.

The patient had a cleft of the soft palate and part of the hard palate, resulting in weak sucking and difficulty in feeding. Artificial feeding was employed, the patient was fed 140mL of milk five times a day. Complementary food was added twice a day: high-iron rice cereal, pumpkin, and broccoli. The stool was thin and yellow with numerous milk flaps. Urination and sleep were normal. The mother denied a history of exposure to pesticides and toxic substances and had no history of special diseases during pregnancy. Physical examination determined the following: temperature: 36.5°C, weight: 6.50 kg (3-15th centile), height: 61.0 cm (0-1th centile), bregma: 4×4 cm, full fontanelle, and normal pressure, conscious and responsive. A small pinpoint-like red rash could be seen on the face, and a dense erythematous rash, with a rough surface, scaly, and irregular edges, without blisters, erosions, and exudates could be seen on the back. No obvious rash was observed on the skin of the limbs, which had a rough and dry surface. Breath sounds in both lungs were coarse, with no obvious rales. Auscultation in the precordial area, a grade 4 holosystolic murmur, and the circulation of the extremities could be heard.

Peripheral blood cell examination showed a white blood cell count 14.0×10⁹/L, neutrophil percentage 42.9%(↓), lymphocyte percentage 45.4%(↑),red blood cell 2.34×10¹²/L, hemoglobin concentration 106g/L(↓), and platelet count 591×10⁹/L(↑), C-reactive protein 0.91mg/L. Echocardiography noted a atrial septal defect. Left ventricular systolic function index: the measured value was normal; the Color Doppler ultrasound of the liver, gallbladder, pancreas, and spleen showed no abnormal sonography. The Color Doppler portal vein and splenic vein blood flow signals were not abnormal. Craniocerebral ultrasound showed hydrocephalus. Cranial CT showed dysplasia of corpus callosum (absent pressure); the left temporal minimal arachnoid cyst was considered. Auditory brainstem response showed 50dBnHL elicited waves in the right ear and 70dBnHL elicited waves in the left ear (Fig. 1).

Gesell Score: Adaptation: 23; Gross Motor: 30; Fine Motor: 25; Language: 14; Personal-Social: 23. Suggests severe mental retardation.

Document Retrieval

The keywords "chromosome 4q deletion syndrome", "4q deletion syndrome", and "4q21 deletion syndrome" were searched through Pubmed and Web of Science Databases. The keywords "chromosome 4q deletion", and "chromosome 4 deletion" were searched in the CNKI databases. The document retrieval time is June 30, 2022, import NoteExpress3.5 document management software to screen duplicate and unrelated documents.

Genetic Test

A total of 2mL of peripheral blood were drawn from the children and their parents. DNA was extracted using Qiagen DNA Mini Kit, and DNA quality was checked by Nanodrop2000 (Thermal Fisher Scientific, USA). Using the S220 Focused-ultrasonicator instrument, 1–3µg of genomic DNA was split into fragments with an average size of 150bp, and the fragments were subjected to end repair, adapter ligation, and PCR amplification to construct a DNA library. DNA libraries were captured using the Whole Exon Capture Kit (MyGenostics, GenCap) and then sequenced by the DNBSEQ sequencer. The raw data generated by sequencing was saved in FASTQ format. low-quality sequences were filtered by CutAdapter software, and Sentieon BWA software was used to align the filtered sequences to the UCSC database human reference genome sequence (hg19) and detect SNP and InDel variants. The detected variants were annotated with multiple databases, such as 1000 genome, ESP6500, dbSNP, EXAC, Inhouse (Mygenics), HGMD, and SIFT by ANNOVAR software (http://annovar.openbioinformatics.org/en/latest/). PolyPhen-2, MutationTaster, GERP + + were used for pathogenicity prediction. The obtained loci were identified as pathogenic by ACMG guidelines.

After the filtered sequences are aligned to the human reference genome sequence (hg19) of the UCSC database, the sequencing depth of each captured region was obtained, and the intra-sample normalization and correction (GC correction and repetitive region correction) were performed. The optimal control sample was obtained by the k-mean method, the sample was normalized and the copy number of each region was calculated, the regions were merged by the binary segmentation algorithm and the copy number information was obtained. All obtained suspected deletion repeat regions are compared with databases such as OMIM, GeneReviews, Decipher, ClinVar, DGV etc, to obtain phenotypic information related to chromosomal regions. Pathogenicity of copy number variations (CNVs) determined by ACMG guidelines and validation of parental samples using low-depth whole-genome sequencing.

Literature Search and Results

The literature search yielded a total of 213 articles, in which the screening was repeated and unrelated, and 40 articles were closely related to the keywords (Fig. 2).Genotypes reported in the relevant literature can be found in Table 1.

Genetic Test Results

Whole exome showed that the patient had a 9.806 Mb copy number deletion at chromosome 4q (Fig. 3). The key region ranges from chr4:74719488–84525945, and the deletion region includes several RefSeq genes, such as HNRNPDL, PRKG2, RASGEF1B, ANTXR2, COQ2, FRAS1, ODAPH, SCD5, etc. (Fig. 4). The CNV results of both parents showed no fragment deletion, which verified that the patient's gene deletion was congenital and that there was no parental inheritance.

According to the clinical manifestations of the child, combined with cytogenetic and CNV analysis of the parents (Fig. 5), the child was diagnosed with 4q13.3–q21.23 deletion syndrome.

Chromosome 4 gene deletion syndrome is a clinically rare chromosomal disorder, which is divided into 2 types according to the region of 4q deletion, including long arm terminal deletion and proximal midsection deletion. Both deletion types have a highly variable clinical phenotype, but terminal deletion cases exhibit a wider range of phenotypes[5, 6]. Proximal microdeletion syndrome on the long arm of chromosome 4 is only rarely reported, and the clinical manifestations also vary among individuals. The most common ones are intellectual disability and congenital anomalies [1].

When Bonnet et al.[7] compared 9 unrelated individuals with 4q21 microdeletion syndrome, they concluded that neonatal intellectual disability, growth restriction, and congenital defects are their common characteristic manifestations. The deletion includes 5 RefSeq genes and identifies PRKG2 and RASGEF1B as major determinants of the 4q21 deletion phenotype, key genes for intellectual disability and language deficits. Subsequently, a study by Hu Xuyun [8] confirmed the view that PRKG2 and RASGEF1B are key genes, in 3 cases of 4q21 deletion identified by clinical chromosomal microarray analysis. In addition, this study also found that the heterogeneous nuclear ribonucleoprotein HNRNPD and HNRNPDL genes are associated with growth retardation and hypotonia. A case of 4q21 deletion in Texas also found the above-mentioned consistent PRKG2 and RASGEF1B key genes[9]. Since then[10], the case of a Canadian 18-year-old boy patient has defined a minimal critical region within the chromosome 4q deletion region, and the data suggest that HNRNPD and HNRNPDL may be the key genes that cause cerebral palsy and myopathy, which is consistent with the findings of Hu Xuyun. In several cases, PRKG2 was reported as a key gene for language defects in the 4q21 deletion region, which encodes cGMP-dependent protein kinase II (cGKII). Therefore, in Germany in 2021[11], a mouse model with 4q21 deletion of key genes was established to verify whether the knockout of cGKII affected vocalization. The experiment found that the established mouse model was consistent with the case. From a pathophysiological perspective, the mechanism underlying the clinical manifestations of 4q21 deletion (language deficit) has been confirmed.

In a Lithuanian family [12], the 4q13.3 microdeletion was detected in three affected individuals with the common clinical manifestations of short stature, congenital heart defects, and mild facial abnormalities. ADAMTS3, ANKRD17, and RNU4ATAC9P were screened in key regions of gene defects as candidate genes for intellectual disability, growth retardation, and congenital heart defects. Quintela [13] found the key genes UBA6 and EPHA5 in the 4q13.2 deletion region and determined that UBA6 is a strong candidate gene for intellectual disability and behavioral disorders. It has not been established whether the EPHA5 gene is associated with autism symptoms. In a case of 4q13.1-q13.3 microdeletion in Hunan Provence [14], the clinical manifestations of the patient have certain commonalities with the previous cases. However, the relationship between genotype and phenotype cannot be determined because the key genes in the deletion region have not been identified. In a previous report, 4q13.3 deletion syndrome often accompanies a co-deletion of 4q21, resulting in significant growth restriction and severe intellectual disability. Only a few cases of 4q13.3 deletion do not involve unrelated 4q21 regions[15].

The cytogenetic results of this case involve the deletion of a known haploinsufficiency-susceptible gene, and the gene deletion phenotypes involved in multiple case reports are consistent and highly specific. The variant is a suspected pathogenic variant. Clinically, the child suffers from congenital heart disease, with atrial defect as the main factor, cleft palate, absence of the corpus callosum, secondary lateral ventricle enlargement, and possibly hydrocephalus. The child has clinical manifestations related to hydrocephalus, and the color Doppler ultrasonography of the brain indicates the presence of the condition, but the MRI does not. Considering the possibility of artifacts on color Doppler ultrasonography, the diagnosis should be treated with caution. Judging from the physical examination and birth status, the child has progressive growth retardation in the growth process, a 7-month-old neck erection that presents a problem, the sitting position is leaning forward, and the motor development is significantly behind normal children of the same age. The child has a congenital malformation of the corpus callosum, the Gesell results show that the scores of the five energy areas are all very low, which can confirm the intellectual disability of the child, and deletion of key genes PRKG2, RASGEF1B, and HNRNPDL in the chromosome 4q13.3-q21.23 deletion region. These results are consistent with previous literature. The reported results are consistent, and there is a correlation between genotype and phenotype. In this case, during the development process of the child, the caregiver should pay more attention to the development of the five energy areas of intellectual development, and take timely intervention measures. Chen[16] reported the molecular and cytogenetic features of a 2-year-old girl with a proximal deletion of chromosome 4q12-q21.21, confirming that haploinsufficiency of the BMP2K gene may lead to ocular disease and that EREG, AREG and BTC haploinsufficiency may lead to delayed puberty in patients. In 2015, Hemati[17] published a 4q12-q21.21 deletion genotype-phenotype correlation study. It is believed that Chen et al. hypothesized that the sample size of this study was insufficient and lead to weak convincing. In this Canadian study, a patient with a 24.89 Mb deletion does not have BMP2K gene deletion, but has various eye-related problems. Therefore, we reviewed 128 hemizygous gene profiles (ESTs), none of which were associated with ocular abnormalities, and concluded that the patient's ocular problems could not be attributed to haploinsufficiency in one or more of these genes. In addition, substantial experimental evidence confirms that BMPs inhibit the visual field lineage, and that lens-derived BMP activity maintains visual field properties during early neural tube stages and induces neural retinal cells in forebrain age[18]. Furthermore, BMP signaling is involved in the formation of bony structures in the ear and membranous labyrinth, so BMP3 may still be considered a deaf candidate[19]. In this case, the patient with BMP2K gene deficiency but normal fundus examination supports the findings of Hemati et al. Eye lesions cannot be ruled out, and regular eye examinations are required.

A previous review on terminal 4q deletion syndrome concluded that, in addition to the high phenotypic variation in cases with overlapping interspace deletions, chromosomal 4q deletion syndromes are commonly characterized by intellectual disability, craniofacial deformities, and rotated or low-set ears[6]. In addition, a SCD5 mutation was found in a Chinese family with familial neurological hearing loss, and SCD5 was identified as a new therapeutic gene for autosomal dominant nonsyndromic hearing loss by whole exome sequencing[20, 21]. A study by Sundagumaran[21] on anemic and non-anemic ears confirmed that iron deficiency anemia (IDA) has a lasting effect on the central auditory system when IDA persists. In this case, the routine blood tests of the child showed that the hemoglobin concentration was lower than normal and the platelet count was increased. Anemia in the ear can be considered. There is a deletion of the SCD5 gene in key regions. The hearing loss of the child may be caused by anemia and chromosomal deletion in both directions. The child had a congenital cleft lip and palate. In a previous study on the 4q major deletion, the proportion of cleft lip and palate manifestations was 37% [22]. It is well known that cleft lip and palate is a phenotype caused by multiple genotypes, making it difficult to draw conclusions about our patient from these larger deletion series[23, 24]. However, an inversion of chromosome 4 was found in a father and son with cleft lip, which disrupted the SCD5 gene, which is not part of the critical region. Nevertheless, it has been deleted in other patients with 4q21 microdeletion syndrome, further expanding the phenotype and may be related to the deletion of the SCD5 gene, and more research is needed to determine the contribution and involvement of this gene in the clinical expression of this syndrome[25, 26].

In this case, the deleted genes ANTXR2, FRAS1, ODAPH, and SCARB2 in the region did not find corresponding clinical manifestations in chromosome 4q deletion syndrome. ANTXR2 and ODAPH genotypes were associated with poor enamel and gingival fibromatosis[27, 28]. FRAS1 is the genotype of Fraser Syndrome[29, 30] and gene mutations in SCARB2 cause autosomal recessive progressive myoclonic epilepsy[31]. In individuals with proximal 4q deletions, intellectual disability or developmental delay is observed across all trait assessments, and neurological functions attributed to haploinsufficiency of genes expressed in the brain may explain many of the cognitive and behavioral traits in patients with this deletion[17]. Developmental delay is common in patients with corpus callosum hypoplasia, especially in higher cognitive and social functions, and deficits in the social cognitive domain are predisposed to manifest as behavioral problems [32, 33]. Therefore, it is recommended to use non-verbal communication techniques for early intervention, and the development of social communication skills in children at an early stage may improve the quality of life of some individuals with 4q deletion.

Table 1

4q13–21 deletion syndrome patients with chromosomal microdeletion regions and deleted genes.
Literature	Patient	Year of publication	Chromosomal region	Missing length/Mb	Missing gene
Nowaczyk MJ[34]	1, 2	1997	4q21.3-q23 4q13.2-q23	/	/
Harada N[35]	3	2002	4q21-q22	/	BMP3, PRKG2, MEPE, IBSP, DSPP
Velinov M[36]	4	2005	4q21.1-q21.3	/	PKD2
Hedera, P[37]	5, 6	2007	4q13-q21	7	SCC4A, CCNI
Bonnet C[7]	7, 8, 9, 10, 11, 12, 13, 14, 15	2010	4q21	1.37	PRKG2, RASGEF1B, HNRNPD, HNRPDL, ENOPH1
Lipska BS[15]	16	2011	4q13.3-q21.23	8.6	BMP3, PRKG2和RASGEF1
Bhoj E[25]	17, 18	2013	4q21.21-q21.23	1.37	RASGEF1B, HNRNPD, HNRPDL, ENOPH, SCD5, THAP9, COQ2
Hemati P[17]	19, 20, 21, 22, 23	2015	4q12-4q21.21	24.89	KIT, AMTN, ENAM, AMBN
Quintela I[13]	24, 25, 26	2015	4q13.2	3.84	EPHA5, UBA6
Lebedev.IN[38]	27	2016	4q21.21-q21.22	1.61	BMP3, PRKG2, RASGEF1B, HNRNPD, HNRPDL, ENOPH1, TMEM150C, SCD5
YANG Ning[9]	28, 29, 30, 31, 32	2016	4q21-q22	15.26	PRKG2, RASGEF1B, HNRNPD, HNRNPDL, ENOPH1, FGF5, PTPN13, SNCA, FAM175A, AGPAT9, MAPK10, PKD2
Hu X[8]	33, 34, 35	2016	4q21	1.37	PRKG2, RASGEF1B, HNRNPD, HNRNPDL
MA Na[14]	36	2016	4q13.1-q13.3	11.6	/
Zarrei M[10]	37	2017	4q21.22	1.3	PRKG2, RASGEF1B, HNRNPDL, HNRNPD, LIN54, COPS4
Maldžienė Ž[12]	38, 39, 40	2020	4q13.3	1.56	ADAMTS3, ANKRD17, COX18, GC, NPFFR2
Chung,WY[39]	41, 42	2020	4q12-q21.1	22.8	SRD5A3, SLC4A4, CEP153
This study	43		4q13.3-q21.23	9.806	ANTXR2, COQ2, FRAS1, HNRNPDL, PRKG2, RASGEF1B, ODAPH, SCARB2, SCD5

We reported a rare case of a child with chromosome 4q deletion and a literature review on the subject. We found that there are many genes within this deletion, but they appear to have no relevant clinical manifestations. Genes like HNRNPDL, PRKG2, RASGEF1B, SCD5 are consistent with a clinical phenotype. However, the phenotypes of ANTXR2, COQ2, FRAS1, ODAPH, and SCARB2 genotypes reported in the literature did not show the corresponding clinical manifestations associated with chromosome 4q deletion syndrome. This shows that the existing molecular biological tests still cannot explain the genotype-phenotype relationship and more advanced genetic testing technology or bioinformatics tools need to be developed. In order to better diagnose and treat these diseases, we need more case evidence to support the clinical signs of chromosome 4q deletion diseases. Information about whether the underlying gene defect will occur, how the pathogenesis mechanism produces corresponding clinical changes, and more clinical cases are needed for analysis.

Author Contributions:Dan Wang and Chuican Huang: Conceptualization, Writing—Original draft preparation ;Qing Luo Methodology Review & Editing; Zhengning Huang Collection of cases; Cheng Zhang Literature search and Review; Lichun Fan critically reviewed the manuscript for important intellectual content and reviewed and revised the manuscript, Funding acquisition; All authors have read and agreed to the published version of the manuscript.

Funding: This study was supported by the Hainan Major Science and Technology Projects of China (No. ZDKJ2019010), the Key Research and Development Program of Hainan Province (Grant No. ZDYF2020210), the Hainan Provincial Natural Science Foundation of China (No.821QN416，No.820QN411), the Excellent Talent Team of Hainan Province (No. QWYH202175) and the Hainan Province Clinical Medical Center (No. QWYH202175)，the Innovative scientific research project for graduate students of Hainan Medical University (No. Hyb2020-60)).

Institutional Review Board Statement: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of Hainan Women and Children’s Medical Center

Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.

Data Availability Statement: Not applicable.

Acknowledgments: The authors would like to thank the children and parents in this study for their cooperation with the study, and those who helped with this study.

Conflicts of Interest: The authors have no conflicts of interest to declare that are relevant to the content of this article.

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Hedera, P.; Blair, M.A.; Andermann, E.; Andermann, F.; D’Agostino, D.; Taylor, K.A.; Chahine, L.; Pandolfo, M.; Bradford, Y.; Haines, J.L.; et al. Familial mesial temporal lobe epilepsy maps to chromosome 4q13.2-q21.3. Neurology. 2007, 68, 2107–2112.
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No competing interests reported.

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Chromosome 4q deletion syndrome: 4q13.3-q21.23 deletion syndrome with mental retardation, congenital heart disease: a case report and literature review

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