A de novo microdeletion of 3q27.1-3q27.2 causing fetal growth retardation: a case report and literature review

Introduction

Chromosomal microdeletion and microduplication syndromes are often linked to intellectual disabilities, multiple congenital anomalies, and/or autism spectrum disorders. Initially, a case report identified and summarized the association between anophthalmia/microphthalmia and distal 3q rearrangements (1). Later, it was found that many of these patients were also affected by fetal growth restriction (FGR), as well as failure to thrive and other developmental issues. FGR can be caused by various factors, including maternal illnesses, placental dysfunction, and fetal genetic factors (2-5). Once FGR is diagnosed, microarray and chromosomal analyses are conducted via amniocentesis to rule out common causes of FGR. A strong correlation exists between FGR and chromosomal abnormalities. In certain microdeletion or microduplication syndromes, FGR may serve as a primary or even sole manifestation (6,7). A chromosomal region associated with FGR has been identified at 3q26-3q28. Microdeletions in this region are rare and not well understood, with only 11 cases reported in the literature to date (8-15). We report a patient with dysmorphic features because of deletion involving 3q27.1-3q27.2. She has asymmetrical bilateral eye clefts and susceptibility to liver function abnormalities that have not been reported in other case reports.

Despite varying breakpoints, patients exhibit a distinct phenotype including FGR, microcephaly, short stature, facial abnormalities, and feeding difficulties. The clinical significance and genetics of 3q26-3q28 microdeletion remain unclear. This study reports a case with overlapping microdeletions, refining the smallest region of overlap (SRO) to a 0.33 Mb segment at 3q27.1 through high-resolution single nucleotide polymorphism (SNP) microarray analysis. This SRO encompasses 46 genes, including 24 annotated in online mendelian inheritance in man (OMIM) and seven associated with disease [Eukaryotic Translation Initiation Factor 2B Subunit Epsilon (EIF2B5), Dishevelled Segment Polarity Protein 3 (DVL3), Adaptor Related Protein Complex 2 Subunit Mu 1 (AP2M1), Alpha-1, 3-Mannosyltransferase (ALG3), Eukaryotic Translation Initiation Factor 4 Gamma 1 (EIF4G1), Chloride Voltage-Gated Channel 2 (CLCN2), and Thrombopoietin (THPO)]. We present this article in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2024-546/rc).

Case presentation

Clinical presentation and clinical course

The patient is a 10-month-old girl who was admitted to the West China Second University Hospital due to severe malnutrition at 10 months of age. The patient is the first child born to non-consanguineous Chinese parents. Family history includes father with oligospermia and thyroid cancer, grandmother with lung cancer, and great-grandmother with colon cancer. Fetal ultrasound at 28 weeks of gestation detected FGR, but the fetus appeared structurally normal, and no placental abnormalities were found, and umbilical artery blood flow remained normal. In the late pregnancy, head circumference remained at −3.7 standard deviation (SD) in two measurements. Fetal and postnatal brain magnetic resonance imagings (MRIs) showed no structural abnormalities. At gestational age (GA) 36 weeks 5 days, ultrasound detected polyhydramnios with an amniotic fluid index (AFI) of 30 cm and a maximum vertical pocket (MVP) of 11.2 cm. A follow-up ultrasound at GA 38 weeks 5 days, showed an improvement in polyhydramnios, with an AFI of 22.05 cm and an MVP of 9.1 cm. After 33 weeks, fetal growth slowed but remained on the normal curve. The obstetrician recommended delivery at 40 weeks. Amniocentesis revealed a 3q27.1-3q27.2 deletion (chr3:184135386-185698347). The mother had subclinical hypothyroidism and was anti-cardiolipin antibody positive during pregnancy. The delivery occurred at 40 weeks of gestation, with all growth parameters falling below the third percentile: birth weight was 1870 g (−3.0 SD), length was 43 cm (−3.0 SD), and occipitofrontal circumference (OFC) measured 31 cm (−3.0 SD). Apgar scores: 10-10-10. Physical exam showed small eye fissures, bilateral eye cleft asymmetry, patent ductus arteriosus (PDA), and mild-to-moderate tricuspid regurgitation (Figure 1). By five months, PDA had closed, but a bicuspid aortic valve with turbulent flow was detected. Neonatal hospitalization was required for hypoglycemia, abnormal liver function, and pathological jaundice. Regular follow-ups were recommended. After discharge until the age of 10 months, she suffered from respiratory tract infections three times, one of which was the 2019 novel coronavirus (2019-nCoV) infection, and sputum culture indicated Escherichia coli. Liver function abnormalities occurred at birth and during infections but recovered quickly. She has three teeth and no abnormalities in skin, hair, genitalia, or limbs. Physical exam showed small eye fissures and asymmetric eye clefts. Language, cognition, and social development are normal, with fine motor skills adequate, but gross motor skills are significantly delayed compared to peers. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient’s legal guardian for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 1 Facial images of the described patient at the age of 10 months. The front view shows small eye fissures and asymmetry in the bilateral eye clefts. This image is published with the consent of child’s legal guardian.

Microarray analysis of amniotic fluid DNA is used to assess the fetal genome and health. Amniotic fluid, containing fetal DNA, is collected via amniocentesis. DNA is extracted, followed by microarray hybridization and data analysis, providing genomic insights. Chromosomal microarray analysis identified a 1.56 Mb deletion on the long arm of chromosome 3 (arr [hg19] 3q27.1-3q27.2 (184,135,386–1851,698,347)x1).

Given the observed malnutrition, pediatricians initiated nutritional interventions from the neonatal period. The infant was exclusively breastfed, then given fortified breast milk and premature formula. Despite low intake without reflux, she accepted solid foods at six months, but catch-up growth was absent. Swallowing function was normal. By 10 months of age, the proband’s growth parameters remained below the 3rd percentile; weight: 5 kg (P≤0.1st centile, Z value: −3.95 SD, as shown in Figure 2A); length: 64.8 cm (P: 0.1st centile, Z value: −2.95 SD, as shown in Figure 2B); OFC: 38 cm (P≤0.1st centile, Z value: −5.08 SD, as shown in Figure 2C). Growth hormone therapy was considered but declined by the parents. Regular rehabilitation was advised, and with continuous therapy, all functional domains are now within the normal range. The parents, reassured after understanding the condition, remain focused on rehabilitation. No adverse effects or unexpected events have occurred.

Figure 2 Weight (A), length (B) and OFC (C) of this infant for first 10 months of life. Measurements are plotted on WHO growth charts with 97th, 85th, 50th, 15th and 3rd growth percentile curves. Black X marks represent the patient’s recorded measurements at different ages. OFC, occipitofrontal circumference (head circumference).

Discussion

The patient in this report carried a 1.56 Mb microdeletion at 3q27.1-3q27.2, offering new insights into recently identified microdeletion syndromes in the distal 3q region. We have summarized similar distal 3q deletions that partially overlap with our case (Figure 3). The proband exhibited several clinical features consistent with those reported in previous cases, including FGR with microcephaly, postnatal growth retardation, and delayed gross motor development. With the shortest chromosomal deletion, she lacks some features seen in other cases, such as abnormal hair, genital malformations, infections, epilepsy, and limb abnormalities. However, she presents unique traits, including asymmetrical eye clefts and liver function susceptibility. Tables 1,2 summarize observed features, highlighting FGR as the most consistent. This case reinforces that 3q26.33-3q27.3 deletions can cause a severe phenotype, often detectable in utero.

Figure 3 Schematic representation of chromosome 3q26.33-3q28 region showing previously reported deletions, deletions described in this study, and SRO. Genome assembly: the genomic coordinates are based on GRCh37/hg19. Special notes: each horizontal bar represents a reported case of 3q26.33-3q28 deletion. The red vertical lines highlight the critical SRO. M, megabases; SRO, smallest region of overlap.

By analyzing the microarray findings from these 11 cases, we identified the SRO as a 0.33 Mb segment, corresponding to genomic coordinates 184,135,386–184,469,308 (hg19) (Figure 3). Deletions overlapping this region are not present in population databases, including database of genomic variants (DGV) Gold Standard (16,17). The SRO region contains seven disease-related genes, including EIF2B5, ALG3, DVL3, AP2M1, THPO, CLCN2, and EIF4G1. Autosomal recessive diseases require mutations in both gene copies for manifestation. A single-copy deletion may make an individual carrier without symptoms, but if the other copy is mutated, the disease appears. ALG3 and EIF2B5, linked to autosomal recessive disorders, likely contribute less to the phenotype. Instead, DVL3, AP2M1, and EIF4G1 may be involved. FGR was present in three cases with SRO deletions, but absent in a case excluding the SRO, supporting FGR-related genes in this region. Additionally, haploinsufficiency of dosage-sensitive genes may mitigate clinical severity, warranting further study.

The CLCN2 gene’s inheritance is not strictly dominant or recessive. Its protein regulates chloride ion permeability, and mutations can cause CLCN2-related epilepsies with varied inheritance patterns. Similarly, THPO gene mutations, affecting thrombopoietin, also follow diverse inheritance modes.

The EIF4G1 protein plays a crucial role in the formation of the translation initiation complex, which is a key step in the process of protein synthesis. Mutations in the EIF4G1 gene have been linked to several neurodegenerative disorders, such as Parkinson’s disease and essential tremor.

In addition to the previously analyzed genes, the chromosomal deletion in this case also involves insulin like growth factor 2 messenger RNA (mRNA) binding protein 2 (IGF2BP2), Lipase H (LIPH), and Enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (EHHADH). IGF2BP2 is a gene that encodes a protein involved in the regulation of mRNA translation and stability, particularly related to insulin signaling and glucose metabolism. Variations in the IGF2BP2 gene have been linked to a higher risk of developing type 2 diabetes. EHHADH is a gene that encodes the EHADH protein. The EHADH protein plays a role in beta-oxidation in the human body, which is a key step in the fatty acid oxidation pathway. Mutations in the EHHADH gene can lead to metabolic disorders, such as short-chain enoyl-CoA hydratase deficiency. LIPH is an autosomal recessive genetic gene, mutations in which can lead to impaired function of the LIPH enzyme, thereby affecting hair follicle development and healthy hair growth, resulting in hypotrichosis, characterized by sparse, fragile, and easily breakable hair.

DVL3 gene encodes the Dishevelled-3 protein, which plays a crucial role in cell signaling pathways, particularly in the Wnt signaling pathway. The Wnt signaling pathway is essential for processes such as embryonic development, cell polarity, and cell fate determination (18-21). Mutations in the DVL3 gene may affect the Wnt signaling pathway, thereby influencing embryonic development and skeletal formation, leading to the occurrence of Robinow syndrome. Robinow syndrome is a rare and heterogeneous condition defined by short stature, shortened limbs, craniofacial and oro-dental abnormalities, vertebral segmentation defects, and often genital hypoplasia (22). The AP2M1 gene encodes the AP-2 subunit µ1, a key player in cellular endocytosis, essential for growth, metabolism, and nutrient uptake. Loss of AP2M1 may disrupt endocytosis, impacting development. However, studies mainly link AP2M1 to cancer and epileptic encephalopathy. More research is needed to verify the specific impact and related mechanisms of AP2M1 on growth and development (23).

Genes in the previously reported deletion segment show no significant link to liver function abnormalities. However, partial chromosomal microdeletions may impact gene expression in the unaffected region via structural changes, 3D chromosomal alterations, or loss of regulatory elements (24). The following three genes are all located on chromosome 3 and may have an impact on liver function, but the specific mechanisms and effects require further research and validation. Apolipoprotein C3 gene (APOC3) encodes a protein related to lipoprotein metabolism, which may be associated with lipid metabolism and liver function (25). Cytochrome P450 Family 3 Subfamily A Member 4 gene (CYP3A4) encodes an important hepatic cytochrome P450 enzyme involved in the metabolism of drugs and many biologically active substances in the liver (26). Solute Carrier Family 22 Member 1 gene (SLC22A1) encodes a membrane transport protein involved in the transport of substances into and out of cells, which may be associated with the excretion of drugs or metabolites in the liver (27). Homeostatic Iron Regulator gene (HFE) is a key regulatory gene involved in iron metabolism in humans. This gene’s protein regulates intestinal iron absorption and release from storage organs like the liver, maintaining iron balance. HFE gene mutations can cause hereditary hemochromatosis, leading to excessive iron accumulation in tissues, including the liver. This iron overload can damage liver function and result in liver abnormalities such as liver fibrosis, cirrhosis, and liver cancer (28).

Asymmetry in the bilateral eye clefts in this case reports, SRY-Box Transcription Factor 2 (SOX2) gene can be discussed. Microphthalmia and anophthalmia have been reported in case studies involving deletions in the distal region of the long arm of chromosome 3, which include the SOX2 gene (1,29). SOX2 was not deleted in our proband but is located on chromosome 3, adjacent to the deleted segment. It is linked to optic nerve hypoplasia and syndromic microphthalmia, a severe eye malformation. As a key transcription factor, SOX2 is crucial for embryonic development and adult physiology. The SOX2 gene plays a critical role in the early stages of vertebrate eye development by contributing to the specification of the eye field within the anterior neural plate (30-32). Subsequently, Sonic hedgehog (Shh) signaling divides this single eye field into two structures known as optic sulci, which interact with the adjacent surface ectoderm to give rise to the retina and lens (33). Proper spatiotemporal expression of essential transcription and signaling factors is crucial for these developmental processes; disruptions in their expression can lead to congenital ocular abnormalities (34).

This single-case study is limited by its small sample size, hindering definitive genotype-phenotype correlations. No functional studies were conducted to confirm the roles of DVL3, AP2M1, or other candidate genes in FGR and developmental abnormalities. Larger cohorts and in vitro/in vivo models are needed for validation. Despite these limitations, our study refines the 3q26-3q28 microdeletion critical region and suggests potential long-range cis-effects on gene expression, particularly in liver function, providing insights for genetic counseling and clinical management.

Conclusions

This study identifies a 0.33 Mb critical region in 3q27.1-3q27.2, with DVL3 and AP2M1 as key candidate genes for FGR and developmental delay. Notably, we first report a potential link between this microdeletion and liver function abnormalities, suggesting long-range cis-effects on gene expression. Our findings refine the phenotype of 3q26-3q28 microdeletion syndrome and provide new insights into its pathogenic mechanisms, guiding future research and genetic counseling.

Acknowledgments

The authors thank the patient and family for their courage and for allowing the collection of valuable data on the disease’s causes and potential treatments.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2024-546/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2024-546/prf

Funding: This study was supported by the Education Informatization and Big Data Center of Sichuan province (grant No. DSJZXKT181), and the projects of Sichuan University (Nos. 23H0460, 21H0780).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2024-546/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient’s legal guardian for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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