A novel ZRS mutation leads to preaxial polydactyly type 2 in a heterozygous form and Werner mesomelic syndrome in a homozygous form.

Point mutations in the zone of polarizing activity regulatory sequence (ZRS) are known to cause human limb malformations. Although most mutations cause preaxial polydactyly (PPD), triphalangeal thumb (TPT) or both, a mutation in position 404 of the ZRS causes more severe Werner mesomelic syndrome (WMS) for which malformations include the distal arm or leg bones in addition to the hands and/or feet. Of more than 15 reported families with ZRS mutations, only one homozygous individual has been reported, with no change in phenotype compared with heterozygotes.

Functional, histopathologic and natural history study of neuropathy associated with EGR2 mutations.

Mutations in the EGR2 gene cause a spectrum of Charcot-Marie-Tooth disease and related inherited peripheral neuropathies. We ascertained ten consecutive patients with various EGR2 mutations, report a novel de novo mutation, and provide longitudinal clinical data to characterize the natural history of the peripheral neuropathy. We confirmed that respiratory compromise and cranial nerve dysfunction are commonly associated with EGR2 mutations and can be useful in guiding molecular diagnosis.

Zoom-in comparative genomic hybridisation arrays for the characterisation of variable breakpoint contiguous gene syndromes.

Contiguous gene syndromes cause disorders via haploinsufficiency for adjacent genes. Some contiguous gene syndromes (CGS) have stereotypical breakpoints, but others have variable breakpoints. In CGS that have variable breakpoints, the extent of the deletions may be correlated with severity.

Increased risk for developmental delay in Saethre-Chotzen syndrome is associated with TWIST deletions: an improved strategy for TWIST mutation screening.

The majority of patients with Saethre-Chotzen syndrome have mutations in the TWIST gene, which codes for a basic helix-loop-helix transcription factor. Of the genetic alterations identified in TWIST, nonsense mutations, frameshifts secondary to small deletions or insertions, and large deletions implicate haploinsufficiency as the pathogenic mechanism. We identified three novel intragenic mutations and six deletions in our patients by using a new strategy to screen for TWIST mutations.

EGR2 mutation R359W causes a spectrum of Dejerine-Sottas neuropathy.

Heterozygous mutations in the early growth response gene 2 (EGR2), which encodes a zinc-finger transcription factor that regulates the late stages of myelination, cause myelinopathies including congenital hypomyelinating neuropathy, Dejerine-Sottas neuropathy (DSN), and Charcot-Marie-Tooth disease type 1. We screened 170 unrelated neuropathy patients without mutations involving the peripheral myelin protein 22 gene (PMP22), the myelin protein zero gene (MPZ), or the gap junction protein beta1 gene (GJB1) and identified two DSN patients with the heterozygous mutation R359W in the alpha-helix domain of the first zinc-finger of EGR2. We now report that this mutation is a recurrent cause of DSN, and that expressivity ranges from that typical for DSN to a more rapidly progressive neuropathy that can cause death by age 6 years.