Puffenberger et al. (2012) reported 3 Amish patients, including 2 brothers, with severe psychomotor retardation, intractable seizures, dysmorphic features, and a 'lumpy' skull surface. Patients were hypotonic and had poor feeding in the neonatal period. They had severe ... Puffenberger et al. (2012) reported 3 Amish patients, including 2 brothers, with severe psychomotor retardation, intractable seizures, dysmorphic features, and a 'lumpy' skull surface. Patients were hypotonic and had poor feeding in the neonatal period. They had severe developmental delay with an inability to speak or walk independently. All developed focal or generalized intractable seizures by age 6 months associated with multifocal spike-wave discharges on EEG. Seizures were manifest as dystonic posturing, drop attacks, myoclonic jerks, or generalized tonic-clonic events. Dysmorphic features evolved over time and included a bulbous nose, wide mouth and tongue, broad jaw, short hands, short tapered fingers, and broad thumbs. Other features included hypotonia, strabismus, slow horizontal nystagmus, and weak or absent tendon reflexes. Brain MRI showed ventriculomegaly, thin corpus callosum, white matter abnormalities, and an undulating or 'lumpy' skull surface. The cortical ribbon followed the irregular skull contour. Other variable physical anomalies included subglottic stenosis, aortic stenosis, bicuspid aortic valve, umbilical hernia, and hydrocele.
By homozygosity mapping followed by exome sequencing of Amish patients with severe psychomotor retardation, intractable seizures, and craniofacial dysmorphism, Puffenberger et al. (2012) identified a homozygous mutation in the SNIP1 gene (608241.0001). Six heterozygous carriers of this mutation ... By homozygosity mapping followed by exome sequencing of Amish patients with severe psychomotor retardation, intractable seizures, and craniofacial dysmorphism, Puffenberger et al. (2012) identified a homozygous mutation in the SNIP1 gene (608241.0001). Six heterozygous carriers of this mutation were found among 203 Old Order Amish controls, yielding a population-specific allele frequency of 1.48%. (Puffenberger (2012) stated that the correct population-specific allele frequency data appear in Table 4; corresponding data in the text are incorrect.)