Pelger-Huet Anomaly and Greenberg Skeletal Dysplasia via the LBR Gene

Pelger-Huet Anomaly (PHA) was first reported in the late 1920s and early 1930s and is characterized by hyposegmentation of nuclei and abnormal chromatin organization in blood granulocytes (Pelger, K Ned T Geneesk 72:1178, 1928; Huet, G.H. Maandschr. Kindergeneesk 1:173, 1932). Data suggest PHA is a due to a deficiency of the lamin B receptor protein within the nuclear membrane (Hoffman et al. 2002). The abnormal neutrophils found in PHA patients are reported to function properly (Johnson et al. 1980), but severe (homozygous) forms of the disease may be accompanied by mental retardation and skeletal anomalies including disproportionate body stature, macrocephaly, ventricular septal defect, and short fingers (Hoffman et al. 2002). A related disorder, Hydrops-ectopic calcification-"moth-eaten" (HEM) or Greenberg skeletal dysplasia is characterized by a phenotype similar to that found in severe forms of PHA and may also present with fetal hydrops and abnormal chondro-osseous calcification often resulting in prenatal death (Waterham et al. 2003; Clayton et al. 2010). Since healthy relatives of patients with Greenberg skeletal dysplasia were found to have abnormal granulocyte neuclei, it is suspected that classic PHA and Greenberg skeletal dysplasia represent the heterozygous and homozygous states of lamin B receptor deficiency, respectively (Waterham et al. 2003).

Mutations in the LBR gene are involved with autosomal dominant Pelger-Huet Anomaly (PHA) (Hoffman et al. 2002) and autosomal recessive Greenberg skeletal dysplasia (Waterham et al. 2003). The LBR gene encodes the lamin B receptor which comprises an N-terminal lamin B / DNA-binding domain and a C-terminal sterol reductase-like domain (Holmer et al. 1998). The lamin B receptor is highly conserved evolutionarily and helps maintain the structural integrity of the inner-nuclear membrane through binding to chromatin and nuclear lamins (Burke and Ellenberg 2002). Decreased sterol reductase function of the lamin B receptor is found in Greenberg skeletal dystrophy patients (Waterham et al. 2003) thereby identifying Greenberg skeletal dysplasia as a disorder of cholesterol biosynthesis. The frequency of PHA is around 0.01-0.1% worldwide, but is higher in areas of northern Sweden and southeastern Germany (Hoffman et al. 2002); the frequency of Greenberg skeletal dysplasia is unclear. Causative variants are spread throughout the 13 coding exons of the LBR gene and include roughly equal proportions of missense / nonsense mutations and small deletions or insertions.

The incidence of PHA is around 0.01-0.1% worldwide, but is higher in areas of northern Sweden and southeastern Germany (Hoffman et al. 2002); the frequency of Greenberg skeletal dysplasia is unclear. Only a small number of PHA and Greenberg skeletal dysplasia cases have been reported in the literature so the rate of mutation detection among patients remains unclear.

To date, no large genomic deletions or duplications in the LBR gene have been reported in PHA or Greenberg skeletal dysplasia patients.

This test provides full coverage of all coding exons of the LBR 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).