Pediatricians may be requested to elucidate the cause of nonspecific persistent generalized infantile hypotonia. Among the many causes in the differential diagnosis of a floppy baby are several familiar genetic diseases that can present with generalized hypotonia in the newborn period. Testing for these disorders, spinal muscular atrophy (SMA), myotonic dystrophy (DM) and Prader-Willi Syndrome (PWS), now requires only a small amount of peripheral blood, and positive results are diagnostic for that disease. The tests for SMA, DM, and recently PWS are done by DNA analysis to look for gene deletions(SMA), expansions (DM), or the absence of the paternal copy of chromosome 15(PWS). Previous analysis for PWS, including this study, has been done by chromosome fluorescence in-situ hybridization to look for deletions in the PWS region of chromosome 15. This technique can detect approximately 70% of those with PWS. Screening of 35 persistently hypotonic children for one or more of these three disorders revealed 7 positive results, 2 with DM, 1 with SMA and 4 with PWS, for a detection rate of 20%. In addition, in 8 of 8 cases in which a clinical diagnosis of SMA had been made, DNA analysis was used to confirm the diagnosis, aid in interpretation of prenatal results in subsequent pregnancies, or provide a conclusive diagnosis, without the need for a muscle biopsy. Positive findings for one of these genetic diseases can provide valuable information regarding clinical management and prognosis of the child, allow specific prenatal testing in future pregnancies and could lead to the identification of other at-risk relatives. Twenty per cent of hypotonic infants were found with one of these three genetic disorders, illustrating the significance of considering this panel of diseases in an infant presenting for genetic evaluation with nonspecific hypotonia.