17p13.3 (Miller-Dieker syndrome) region (includes YWHAE and PAFAH1B1)

Bi et al (2009) identified seven unrelated individuals with 17p13.3 microduplications involving the PAFAH1B1 and/or YWHAE genes. They showed that increased PAFAH1B1 dosage causes mild brain structural abnormalities, moderate to severe developmental delay and failure to thrive. Individuals with duplication of PAFAH1B1 but not YWHAE or CRK show microcephaly and severe growth restriction, but are not particularly dysmorphic. Common features observed in individuals with PAFAH1B1 duplications include neurobehavioral deficits and subtle brain abnormalities. Duplication of YWHAE and surrounding genes increases the risk for macrosomia, mild developmental delay and pervasive developmental disorder, and results in similar facial dysmorphisms. Parental analysis showed that the duplications in subjects 1, 3, 4, 6 and 7 were de novo; in subject 5, it was maternally inherited, and for subject 2, only one normal parent was available. Transgenic mice conditionally overexpressing LIS1 in the developing brain showed a decrease in brain size, an increase in apoptotic cells and a distorted cellular organization in the ventricular zone, including reduced cellular polarity but preserved cortical cell layer identity.

Roos et al (2009) identified three children with overlapping de novo 17p13 microduplications sizes from 1.8 to 4.0 Mb, with a region of overlap corresponding to 1.8 Mb (including the PAFAH1B1 gene). Common clinical features include mild to moderate developmental delay, hypotonia, and similar facial dysmorphism. They did not display lissencephaly or gross brain malformations.

Curry et al (2013) reported nine individuals with larger duplications that involved most of 17p13.3 (Group 2) and four individuals with small centromeric duplications involving chr17:2,000,000–3,000,000 that include PAFAH1B1 and flanking genes (Group 3). Group 2 duplications: 5 de novo, 2 maternal, and 1 paternal Group 3 duplications: 2 de novo, 1 paternal, 1 maternal. The authors described highly variable clinical phenotypes (with inter- and intrafamilial variability), especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and PAFAH1B1. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis, and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications.