Primordial Dwarfism via the POC1A Gene

Primordial dwarfism (PD) is characterized by severe intrauterine and postnatal growth retardation that includes Seckel Syndrome, Silver-Russell Syndrome, Microcephalic Osteodysplastic Primordial Dwarfism types I/III, II and Meier-Gorlin Syndrome (Khetarpal et al. 2016). POC1A-related Primordial Dwarfism is called SOFT syndrome, an abbreviation for short stature, onychodysplasia, facial dysmorphism, and hypotrichosis. The major clinical features include short and thick long bones, short femoral neck, and hypoplastic pelvis and sacrum, long, triangular face with prominent nose and small ears, along with sparse hair, and nail hypoplasia (Shaheen et al. 2012; Koparir et al. 2015). Extreme dyslipidaemic insulin resistance and fatty liver were also reported in one patient affected with POC1A-related Primordial Dwarfism (Chen et al. 2015).

POC1A-related primordial dwarfism is an autosomal recessive disorder. POC1A encodes a centriolar protein which plays multiple key roles in centriole biogenesis (Keller et al. 2009). Abnormal mitotic spindles and centrosome amplification were found in patients’ fibroblasts carrying POC1A pathogenic variants (Shaheen et al. 2012; Koparir et al. 2015; Chen et al. 2015). To date, only 4 unique homozygous pathogenic variants were reported in 7 consanguineous PD families. The c.241C>T, p.Arg81* variant was found in three Saudi families; the c.512T>C, Leu171Pro was reported in two Arab families; and the c.358A>G, Thr120Ala and c.1048delC, p.Gln350Argfs*4 were found in one family, respectively (Sarig et al. 2012; Shaheen et al. 2012; Koparir et al. 2015 and Chen et al. 2015; Human Gene Mutation Database).

The mutation detection rate by sequencing should be high, because the four known unique pathogenic variants are missense, nonsense and a small deletion. However, due to limited publications, clinical sensitivity is difficult to predict.

This test provides full coverage of all coding exons of the POC1A 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).