Miller-Dieker Lissencephaly Syndrome via the YWHAE Gene

Miller-Dieker lissencephaly syndrome (MDLS; OMIM 247200) is characterized by lissencephaly, microcephaly, wrinkled skin over the glabella and frontal suture, prominent occiput, narrow forehead, downward slanting palpebral fissures, small nose and chin, cardiac malformations, hypoplastic male external genitalia, growth retardation, and mental deficiency with seizures (Schinzel J Med Genet 25:454-462, 1988, Dobyns et al. Am J Hum Genet 48:584-594, 1991). Lissencephaly is defined as a "smooth brain" with absent gyri (agyria) or abnormally wide gyri (pachygyria) (Brakovich et al. Ann Neurol 1991; 30:139–46). MDLS patients mostly have more severe lissencephaly (complete agyria) than PAFAH1B1-associated lissencephaly patients (OMIM 607432), explained by the deletion of two additional genes, CRK and YWHAE (also known as 14-3-3ε), on 17p13.3 distal to PAFAH1B1 gene (Chong et al. Hum Molc Genet 6:147-155, 1997). Subsequently, it has been documented that the deletion of YWHAE gene is responsible for the greater severity of Miller-Dieker syndrome compared to PAFAH1B1-associated lissencephaly (Toyo-oka et al. Nat Genet 34:274-285, 2003).

Miller-Dieker lissencephaly syndrome is inherited as an autosomal dominant disorder. MDLS is caused by variants in the YWHAE gene (also known as 14-3-3ε) (Toyo-oka et al. 2003; Bi et al. Nat Genet 41:168-177, 2009). The YWHAE gene encodes the 14-3-3-epsilon protein, which binds and protects NUDEL, a phosphorylated protein important in regulating dynein activity in M phase. It has been predicted that 14-3-3-epsilon protein is required for NEDUL localization and cytoplasmic dynein function and might be important for neuronal migration (Toyo-oka et al. 2003). Submicroscopic deletions or duplication of 17p13.3 including PAFAH1B1 and YWHAE have been reported in MDLS patients (Chong et al. 1997; Toyo-oka et al. 2003; Bi et al. 2009). Of note, no point variants in the YWHAE gene have yet been reported in MDLS patients; therefore, aCGH analysis for deletions and duplications within the YWHAE gene should be performed first.

Sensitivity of this test is currently unknown.

This test provides full coverage of all coding exons of the YWHAE gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).