Unraveling the Genetic Spectrum of Hypotonia in Infancy: A Case Series of Three Rare Presentations

A bstract Hypotonia in infancy—commonly termed “floppy infant syndrome”—represents a diagnostic challenge due to its broad etiological spectrum involving central, peripheral, metabolic, and genetic causes. A systematic and stepwise diagnostic approach, incorporating advanced genetic testing, is crucial for timely diagnosis and management. To report three infants presenting with early-onset hypotonia, in whom conventional diagnostic modalities failed, but next-generation sequencing (NGS) revealed rare genetic mutations. We describe three cases of infantile hypotonia evaluated at a tertiary care center, where comprehensive clinical, imaging, metabolic, and molecular investigations were undertaken. Case 1: Identified a heterozygous SCN4A mutation (c.416A>G) linked to congenital myopathy. Case 2: Detected a heterozygous missense mutation in U2AF2 associated with developmental delay, brain anomalies, and dysmorphic features. Case 3: Revealed variants of uncertain significance in DNM2 and VMA21, implicating centronuclear myopathy and autophagic myopathy, respectively. This series underscores the indispensable role of NGS in the diagnostic algorithm for floppy infants and highlights the expanding phenotype–genotype correlations in early-onset neuromuscular disorders.