A de Novo 2q23.1-2q23.3 duplication in a neonate with anemia, thrombocytopenia, and hypospadias: clinical and genomic characterization.

A male infant was born to a healthy 33-year-old mother and a 30-year-old father; he was their first liveborn child. The mother had one previous termination of pregnancy due to a severe thoracoabdominal malformation two years earlier. There was no significant family history, and prenatal care revealed no teratogenic exposures or maternal infections. Pre-pregnancy ultrasound examinations were unremarkable, and chromosomal analysis (amniocentesis, 46, XY, low-resolution 400-band karyotype) showed no abnormalities. At 38 weeks and 4 days of gestation, delivery was performed by cesarean section because of oligohydramnios and increased umbilical artery flow. Given the potential risks associated with oligohydramnios and abnormal umbilical artery flow, including umbilical cord compression, fetal hypoxia, and adverse perinatal outcomes, the clinical team opted for cesarean delivery to mitigate the risk of fetal distress. Table  1 indicates the birth parameters of the patient. Table 1 Key clinical characteristics at birth Birth Metrics Measured Note Birth weight 2150 g < 3rd percentile Body length 46 cm 10th percentile Head circum. 31 cm 3rd -10th percentile Apgar score 10 1–5 min at birth Penile length 2.3 cm Glanular hypospadias Both testes Non-palpable at birth Descended into the scrotum by day 3 of life Key clinical characteristics at birth The infant was admitted to the Neonatal Intensive Care Unit (NICU) for irregular breathing, petechiae, and hematologic abnormalities. Initial laboratory evaluation is summarized in Table  2 . Table 2 Postnatal laboratory evaluation Parameter Measured Normal range Diagnosis Hemoglobin 9.6 g/L 13.4–19.9 g/dL Neonatal anemia Platelet 40 × 10⁹/L 150–450 × 10⁹/L Thrombocytopenia Patent foramen ovale 2.8 mm 1–10 mm Heart rhythm 250–290 bpm 120–160 bpm Supraventricular tachycardia FT3 7.15 pmol/L 3.8–10.0 nmol/L Hypothyroidism FT4 11.19 pmol/L 10.7–39.8 nmol/L Hypothyroidism TSH 21.6 µIU/mL 0.70–15.2 µIU/mL Hypothyroidism FT3: Free Triiodothyronine; FT4: Free Thyroxine; TSH: Thyroid Stimulating Hormone Postnatal laboratory evaluation FT3: Free Triiodothyronine; FT4: Free Thyroxine; TSH: Thyroid Stimulating Hormone Neonatal anemia and thrombocytopenia were treated with transfusions and intravenous immunoglobulin. On day 9, the infant developed supraventricular tachycardia that recurred four times over six days, lasting 1–3 h each episode. Management included intravenous vitamin C, vitamin B6, and adenosine triphosphate (ATP). ATP was rapidly hydrolyzed to adenosine, which transiently inhibited atrioventricular (AV) nodal conduction, terminating the arrhythmia [ 7 ]. Hypothyroidism treatment included oral levothyroxine (10 µg/kg/day), phototherapy, potassium supplementation, and albumin infusion. After four weeks of hospitalization, the infant demonstrated stable respiration without supplemental oxygen, normal thermoregulation, and good feeding tolerance without gastrointestinal symptoms. On discharge, he displayed mild jaundice, a soft anterior fontanelle, and stable vital signs. At 11 months of follow-up, growth and development were appropriate for age. Genetic analysis was performed to investigate potential underlying factors. Peripheral blood DNA from the infant and his parents was sequenced on the Illumina NextSeq 500 platform (NGS, Illumina, San Diego, CA, USA) and aligned to the GRCh37 (Genome Reference Consortium Human Build 37) reference genome. The infant’s genome showed a 1,500 Kb duplication at 2q23.1–2q23.3 (Fig.  1 ). No abnormalities were detected in the mother, whereas the father exhibited a 1,020 Kb duplication at 3p26.3. Both parents were clinically asymptomatic. Fig. 1 Genomic map of the patient’s duplication at 2q23.1–2q23.3 (chr2:149,390,001–150,890,000, GRCh37), spanning approximately 1.5 Mb and including 13 annotated genes. Among these, three are protein-coding ( LYPD6 , MMADHC-DT , RND3 ), three are pseudogenes, and seven are non-coding RNAs. The figure illustrates the precise genomic coordinates and gene distribution within the duplicated region Genomic map of the patient’s duplication at 2q23.1–2q23.3 (chr2:149,390,001–150,890,000, GRCh37), spanning approximately 1.5 Mb and including 13 annotated genes. Among these, three are protein-coding ( LYPD6 , MMADHC-DT , RND3 ), three are pseudogenes, and seven are non-coding RNAs. The figure illustrates the precise genomic coordinates and gene distribution within the duplicated region

Copy number variations (CNVs) contribute significantly to genetic diversity and influence susceptibility to various diseases. In the neonatal patient discussed, a de novo 1.5 Mb duplication was associated with reversible clinical manifestations. Notably, these effects may have occurred independently of a separate 1.02 Mb duplication found in the parent on a different chromosome, suggesting distinct pathogenic mechanisms and highlighting the complexity of CNV interpretation in clinical genetics.

Genomic deletions are more frequently associated with pathogenesis [ 8 , 9 ], though duplications have also been implicated in disease [ 10 , 11 ]. Submicroscopic deletions at chromosome band 2q23.1 have been linked to a syndrome characterized by severe intellectual disability, short stature, microcephaly, and epilepsy, known as 2q23.1 microdeletion syndrome [ 12 ]. The critical overlapping region among affected patients involves only a single gene, MBD5 , which encodes a methyl-DNA binding protein [ 13 ]. Loss of MBD5 is strongly associated with epileptic encephalopathy. By contrast, the duplication identified in our patient is located at 2q23.2, does not involve MBD5 , and instead encompasses 13 other genes (Fig. 1 ). Within this duplicated region, three are protein-coding genes. LYPD6 , a human three-finger protein, functions as a negative modulator of the cholinergic system in the brain [ 14 ]. Its duplication has been linked to developmental delay, hypotonia, and autistic features [ 15 ]. MMADHC-DT , the divergent transcript of MMADHC , is associated with mitochondrial vitamin B12 metabolism [ 16 ]. RND3 , a Rho family GTPase that lacks intrinsic GTPase activity, negatively regulates cytoskeletal organization and cell adhesion [ 17 ]. Increased RND3 expression has also been reported in A2ML1 duplications associated with otitis media [ 18 ]. Together, these genes may have contributed to the diverse neonatal complications observed in the patient, potentially through dosage imbalance or positional effects [ 19 ]. Importantly, the patient’s favorable recovery suggests that these effects may be at least partially reversible. The roles of the three pseudogenes and seven non-coding RNAs (ncRNAs) within this duplication remain unclear, but emerging evidence indicates that pseudogenes can modulate gene expression [ 20 ], and ncRNAs play extensive roles in transcriptional and post-transcriptional regulation [ 21 ]. Thus, these elements may also have contributed to the clinical presentation. The paternal CNV involves a partial duplication of CNTN6 , a glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein of the immunoglobulin superfamily. CNTN6 facilitates axonal connections during nervous system development, and CNVs in this gene have been associated with neurodevelopmental and neuropsychiatric disorders such as ADHD, seizures, and autism spectrum disorder [ 22 ]. However, the paternal CNV includes only the 3′ portion of CNTN6 , which may explain the absence of clinical symptoms. The region also harbors CHL1-AS1 and CHL1-AS2 , antisense RNAs correlated with CHL1 , a gene implicated in ovarian endometriosis [ 23 ]. Along with pseudogenes and ncRNAs, these elements could act as regulatory factors in gene expression [ 20 , 21 ], though in this case their duplication appears phenotypically silent. Interestingly, the paternal CNV was not inherited by the child; instead, the patient carried a distinct duplication on a different chromosome (Fig. 2 ). CNV formation is thought to arise through mechanisms such as non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ), microhomology-mediated end joining (MMEJ), replication slippage, and fork stalling with template switching or break-induced replication [ 24 ]. These processes are influenced by both intrinsic factors (e.g., replication enzymes, ncRNAs, siRNAs) and extrinsic factors (e.g., chemical exposures, ionizing radiation) [ 25 ]. The occurrence of a de novo CNV on a different chromosome highlights the role of non-homologous repair pathways, such as stress-induced fork repair, in CNV genesis [ 24 ]. Fig. 2 Independent occurrence of CNVs in the patient and father. For clarity, only chromosome 2 (depicted as the longer, lower ideogram) and chromosome 3 (shorter, upper ideogram) are shown. Arrowheads indicate the distinct CNV locations: a de novo duplication at 2q23.1–2q23.3 in the patient and a separate duplication at 3p26.3 in the father Independent occurrence of CNVs in the patient and father. For clarity, only chromosome 2 (depicted as the longer, lower ideogram) and chromosome 3 (shorter, upper ideogram) are shown. Arrowheads indicate the distinct CNV locations: a de novo duplication at 2q23.1–2q23.3 in the patient and a separate duplication at 3p26.3 in the father Similar duplications have been reported at 2q23.1–2q23.2 with one overlapped gene LYPD6 . However, one of the patients had a 1.64 Mb duplication starting at chr2: 148 691 798, and the second was a 2 Mb duplication starting at chr2: 148 616 673 [ 26 ]. The case reported here had a 1.5 Mb duplication starting at chr2:149,390,001 (Fig. 1 ), which overlapped with 1,643 CNVs nearby, but matched none exactly in the databases of gnomAD-CNV and Database of Genomic Variants (DGV). While this case provides valuable insight into a rare de novo duplication at 2q23.1–2q23.3, its interpretation is inherently limited by the nature of a single observation, suggesting extreme rarity rather than definitive pathogenicity. Establishing clinical significance for copy number variants (CNVs) typically requires multiple lines of evidence, including case–control data, segregation analysis, and functional studies, which cannot be achieved in an isolated case. Therefore, conclusions drawn from a single case should be considered preliminary and interpreted with caution until corroborated by additional cases or functional validation studies. The fact that the patient’s CNV differs from the paternal CNV in both chromosomal location and gene composition suggests an independent origin, likely during gametogenesis or early embryogenesis. These findings emphasize the unique and complex nature of CNVs and highlight the need for further research into their mechanisms, inheritance patterns, and clinical consequences.

Copy number variations (CNVs) are distributed unevenly in human genome and represent relatively uncommon but important genetic contributors to human disease [ 1 ]. They have been shown to play significant roles in congenital heart disease (CHD) [ 2 ], neonatal birth defects [ 3 ], and more recently in conditions such as pancreatic ductal adenocarcinoma [ 4 ] and osteoporosis [ 5 ]. The genomic region 2q21.1–q23.3 has attracted considerable research attention due to its association with a spectrum of congenital anomalies and developmental disorders, including agenesis of the corpus callosum, congenital cardiac defects, and hypospadias [ 6 ]. Here, we describe a neonatal patient with a novel CNV characterized by a 1,500 Kb duplication at chr2:149390001–150,890,000 (2q23.1–2q23.3), who presented with multiple health issues including neonatal anemia, thrombocytopenia, hypospadias, hyperbilirubinemia, hypokalemia, hypoproteinemia, and neonatal hypothyroidism. The patient showed favorable developmental progress following treatment. Additionally, a separate 1,020 Kb duplication at chr3:60000–1,080,000 (3p26.3) was identified in the father, who remained clinically asymptomatic. The detection was NGS (next generation sequencing) and aligned to the GRCh37 reference genome. The potential relationship between these CNVs, their inheritance patterns, and their contribution to clinical manifestations remains unclear and warrants further investigation.