Recent reviews have emphasized that neurodevelopmental CNVs, including 16p12.2 deletions, demonstrate substantial phenotypic heterogeneity and are associated with diverse cognitive and psychiatric outcomes [5-7]. However, detailed neonatal case descriptions from Korea remain limited, as most Korean data are derived from cohort-level CMA investigations without comprehensive clinical characterization. We present a case of a Korean neonate with a 909 kb recurrent 16p12.2 microdeletion, highlighting neonatal hypotonia, feeding difficulties, and subtle dysmorphic features.

This case was reviewed and approved by the Institutional Review Board (IRB) of Keimyung University Dongsan Hospital (IRB No. 2025-11-048). The requirement for informed consent was waived.

This male infant was born at 37+1 weeks of gestation via cesarean section because of breech presentation. His birth weight was 2.4 kg, which was below the 10th percentile for gestational age, indicating small-for-gestational-age status. The head circumference at birth was 33 cm at 37+1 weeks of gestation, corresponding to approximately the 25th–50th percentile for gestational age. Immediately after birth, he exhibited a weak cry, reduced spontaneous limb movement, and generalized hypotonia.

Feeding difficulties were evident from the neonatal period and were characterized by a weak suck, poor suck–swallow coordination, prolonged feeding times, and intermittent gagging. Inspiratory stridor suggested mild laryngomalacia. Spinal ultrasonography was performed because of a sacral dimple and revealed no abnormalities. Brain ultrasonography was also normal.

Physical examination revealed a small mouth, thin upper lip, increased intercanthal distance, and small hands and feet. Both testes were normally descended. Deep tendon reflexes were present and symmetric. No major structural anomalies were identified.

Because hypotonia and feeding difficulties persisted, CMA was performed at 36 days of age using the CytoScan Dx array platform (Thermo Fisher Scientific, Waltham, MA, USA). CMA identified a 909 kb deletion at 16p12.2 (chr16:21,801,488–22,710,614; hg19), encompassing the ubiquinol-cytochrome c reductase core protein 2 (UQCRC2), eukaryotic elongation factor 2 kinase (EEF2K), and cerebellar degeneration related protein 2 (CDR2) genes (Fig. 1). This deletion fully includes the proximal recurrent region at 16p12.2, which contains EEF2K and CDR2 and has been classified as having emerging evidence for haploinsufficiency by Clinical Genome Resource (ClinGen) curation. The CNV was interpreted as likely pathogenic based on its size, gene content, and prior reports of the recurrent pathogenic interval (Fig. 1). Although parental CMA was offered, it was declined because of financial constraints. Nevertheless, the pathogenicity of the recurrent 16p12.2 deletion can be established regardless of the inheritance pattern [7].

At the most recent outpatient visit at 12 months of corrected age, the patient was alert and interactive. Feeding tolerance had gradually improved; however, mild generalized hypotonia persisted. Developmental assessment indicated motor skills corresponding to approximately 9 to 10 months of age, including independent sitting, reciprocal crawling as the primary mode of locomotion, and the ability to pull to stand through half-kneeling on the right side. Fine motor evaluation demonstrated asymmetric hand use, with relatively reduced function of the right hand. No seizures were observed, and electroencephalography (EEG) demonstrated normal background activity. Early developmental intervention, including physical and occupational therapy, was initiated, and longitudinal follow-up is ongoing. A comparison with previously reported cases is summarized in Table 1.

The recurrent 16p12.2 microdeletion has been associated with a broad spectrum of neurodevelopmental features, including developmental delay, hypotonia, feeding difficulties, growth impairment, and behavioral abnormalities [2-4]. The heterogeneity observed among carriers is consistent with findings from large-scale CNV studies demonstrating variable expressivity and diverse cognitive, behavioral, and psychiatric outcomes [5-7].

Hypotonia and feeding difficulties are often among the earliest recognizable manifestations in affected neonates. These features may reflect immature bulbar coordination and subtle brainstem dysfunction, even in the absence of structural abnormalities or overt metabolic crises. The deleted interval includes several neurobiologically relevant genes—UQCRC2, EEF2K, and CDR2. Although biallelic mutations in UQCRC2 are known to cause severe neonatal metabolic crises [8], heterozygous deletion (haploinsufficiency) may contribute to subtler energetic deficits that manifest as neonatal hypotonia and feeding fatigue, as observed in this patient. However, evidence supporting UQCRC2 haploinsufficiency remains limited compared with its well-established biallelic effects. Heterozygous loss is therefore more likely to function as a contributory factor rather than a primary causal mechanism.

Although some cited studies focus on the 16p12.1 microdeletion, they are referenced to illustrate broader concepts related to recurrent neurodevelopmental CNVs and variable expressivity. The present case specifically involves the recurrent 16p12.2 microdeletion.

Deletions overlapping the 16p12.2 region have been reported in population databases, including the Database of Genomic Variants (DGV) and the Genome Aggregation Database structural variant dataset (gnomAD SV). However, recurrent neurodevelopmental CNVs are well recognized to exhibit incomplete penetrance and markedly variable expressivity. The pathogenicity of the 16p12.2 microdeletion is supported by consistent phenotypic enrichment in affected cohorts, recurrent involvement of dosage-sensitive genes, and replication across independent clinical studies. Therefore, the presence of similar deletions in population databases does not exclude clinical pathogenicity in individual patients.

Growth impairment has been frequently reported in cohorts with 16p12.2 deletions [3,4]. Although this infant was small for gestational age at birth, continued suboptimal weight gain despite improved feeding suggests an intrinsic contribution of the CNV to feeding endurance and metabolic efficiency. Subtle craniofacial features—including a thin upper lip, small mouth, and increased intercanthal distance—are consistent with previously reported dysmorphism associated with this deletion, although such features are often mild and may be easily overlooked in neonates [2-4].

Seizures and EEG abnormalities have been documented in some cases; however, many infants remain seizure-free during early life [2-4]. The absence of seizures and the normal EEG findings in this patient fall within the recognized phenotypic spectrum. Longitudinal follow-up is warranted, as CNVs, including the 16p12.2 deletion, have been associated with neurodevelopmental and behavioral difficulties that may emerge later [5-7].

Although parental testing was not performed, the diagnosis remains valid because the recurrent 16p12.2 deletion is a well-established pathogenic CNV characterized by incomplete penetrance and variable expressivity [7]. Determining inheritance is important for recurrence counseling but does not alter immediate clinical management. Long-term follow-up is ongoing to monitor the patient’s neurodevelopmental trajectory.

Case-level reports of the 16p12.2 microdeletion in Korea remain limited. This neonatal case broadens the clinical spectrum described in Korean infants and underscores the utility of CMA in neonates with persistent hypotonia and feeding difficulties despite normal neuroimaging findings.

We report a Korean neonate with a recurrent 16p12.2 microdeletion who presented with neonatal hypotonia, feeding difficulties, and subtle dysmorphism. Early CMA facilitated diagnosis and informed developmental surveillance. This case contributes to the limited data on Korean patients and underscores the importance of CNV analysis in infants with unexplained hypotonia and feeding dysfunction. Long-term follow-up is ongoing.