Temple-Baraitser Syndrome and Zimmermann-Laband Syndrome via the KCNH1 Gene

Temple-Baraitser syndrome is a rare multisystem developmental disorder characterized by severe intellectual disability, epilepsy, dysmorphic facial features, and hypoplasia or aplasia of the nails of the thumbs and great toes (Jacquinet et al. 2010; Shen et al 2015; Simons et al. 2015).

Zimmermann-Laband syndrome is another rare developmental disorder characterized by facial dysmorphism including coarse face and gingival hypertrophy, hypoplasia or aplasia of nails and terminal phalanges, and hypertrichosis. Intellectual disability has been seen in patients (Kortum et al. 2015).

Temple-Baraitser syndrome and Zimmermann-Laband syndrome share not only the major feature of hypoplasia or aplasia of the nails of the thumbs and great toes, but also other minor characteristics.

Both Temple-Baraitser syndrome and Zimmermann-Laband syndrome are inherited in an autosomal dominant manner. Temple-Baraitser syndrome is caused by pathogenic variants in the KCNH1 gene (Simons et al 2015), while Zimmermann-Laband syndrome is caused by pathogenic variants in the KCNH1 or ATP6V1B2 genes (Kortum et al. 2015). The reported KCNH1 pathogenic variants either in Temple-Baraitser syndrome or Zimmermann-Laband syndrome are missense variants. To date, large deletions or large duplications in KCNH1 have not been discovered (Human Gene Mutation Database).

KCNH1 encodes potassium channel, voltage gated EAG 1 related subfamily H, member 1 (Kv10.1). The gene is predominantly expressed in the adult central nervous system and is thought to be involved in neuronal activity, cell proliferation, and development. De novo pathogenic variants in KCNH1 occur in most cases (Simons et al. 2015). An in vitro study showed Temple-Baraitser syndrome associated pathogenic variants in KCNH1 leads to deleterious gain-of-function in potassium channel activity (Simons et al 2015). Another study also suggests a gain-of-function effect for all Zimmermann-Laband syndrome-associated KCNH1 pathogenic variants (Kortum et al. 2015). When a pathogenic variant in the KCNH1 channel was co-expressed with wild-type KCNH1, it formed heterotetrameric channels which reduced conductance at positive potentials, but also pronounced conductance at negative potentials.

KCNH1 is the only gene known to be involved with Temple-Baraitser syndrome. Compared to Temple-Baraitser syndrome, a molecular cause in KCNH1 was identified in 25% of cases with Zimmermann-Laband syndrome (Kortüm et al. 2015).

This test provides full coverage of all coding exons of the KCNH1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.