Chromosome 17p13.3, Centromeric, Duplication Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene duplication syndrome involving the PAFAH1B1 (LIS1; 601545) and/or the YWHAE (605066) gene on chromosome 17p13.3.

The same region on chromosome 17p13.3 is deleted in Miller-Dieker lissencephaly syndrome (MDLS; 247200).

Clinical Features

Bi et al. (2009) reported 7 unrelated individuals with different submicroscopic duplications of chromosome 17p13.3 involving the LIS1 and/or YWHAE genes. Four individuals had a duplication of YWHAE but not LIS1, and 1 had a duplication of LIS1 but not YWHAE. A sixth patient had a triplication of LIS1, and a seventh had duplication of both genes. Analysis of the clinical features for each individual indicated that individuals with LIS1 duplications had subtle brain defects, including microcephaly, dysgenesis of the corpus callosum, and cerebellar atrophy, as well as neurobehavioral disorders, including delayed development, mental retardation, and attention deficit-hyperactivity disorder. Patients with duplications of YWHAE tended to have macrosomia, facial dysmorphism, and mild developmental delay. Transgenic mice overexpressing Lis1 showed decreased brain size and distorted cellular organization in the ventricular zone. Bi et al. (2009) concluded that variations in dosage of LIS1 play a role in the development of brain anomalies in humans and mice.

Roos et al. (2009) used multiplex ligation-dependent probe amplification (MLPA) or array CGH analysis to identify 3 developmentally delayed children with duplications of chromosome 17p13, ranging in size from 1.8 to 4.0 Mb, with a 1.8-Mb region of overlap. All duplications included the 8 genes in the MDS critical region: PRP8 (607300), RILP (607848), SREC (SCARF1; 607873), PITPNA (600174), SKIP (603055), MYO1C (606538), CRK (164762), and YWHAE. All patients had hypotonia and mild to moderate psychomotor retardation. One had overgrowth, with a marfanoid habitus. Dysmorphic features were present in all 3 patients, including frontal bossing, low-set ears, broad nasal bridge, small nose, hypertelorism, downslanting palpebral fissures, broad and flat midface, and triangularly-shaped chin. The second child, a girl, showed failure to thrive and poor growth. The third child, a boy, also had micropenis, right-sided inguinal hernia, and hypermobility. Brain MRI revealed hypoplasia of the corpus callosum, dilated lateral ventricles, and a suggestion of thinning of the white matter. None of the patients had lissencephaly or gross brain malformations.

Bruno et al. (2010) identified 3 unrelated individuals with a pathogenic microduplication of 17p13.3 from a larger cohort of 7,678 patients who underwent microarray screening for learning difficulties and/or autism with or without other congenital anomalies. Two additional patients from this cohort carried microduplications which were present in unaffected family members, and were thus considered nonpathogenic. Including the patients reported by Bi et al. (2009) and Roos et al. (2009), Bruno et al. (2010) suggested that there are 2 classes of microduplications of 17p13.3. Class I duplications involve YWHAE, but not PAFAH1B1, whereas class II duplications involve PAFAH1B1 and may also include CRK and YWHAE. Class I duplications are associated with autistic features and other behavioral symptoms, speech and motor delay, subtle dysmorphic facial features such as pointed chin and cupid bow, subtle hand/foot malformations, and a tendency to postnatal overgrowth. Class II microduplications are associated with moderate to mild developmental and psychomotor delay and hypotonia. Some dysmorphic features, such as prominent forehead and pointed chin, are shared with the class I duplications. Notably, individuals with duplication of PAFAH1B1 but not YWHAE or CRK show microcephaly and severe growth restriction, but are not particularly dysmorphic. All the breakpoints were nonrecurrent.