Focal Dermal Hypoplasia (FDH) via the PORCN Gene

Focal dermal hypoplasia (also called Goltz syndrome or Goltz-Gorlin syndrome) is a multiorgan developmental disorder primarily affecting the skin and digits, eyes and teeth. Skin defects include congenital dermal atrophy, cutis aplasia; cutaneous soft, yellow-pink fat nodules, abnormal pigmentation and papillomas. The abnormal pigmentation usually follows the lines of Blaschko. Papillomas usually form around the nostrils, lips, anus, and female genitalia. Skeletal defects include oligodactyly, split hand and foot, syndactyly, and ectrodactyly. Ocular defects are anophthalmia and microphthalmia, coloboma in the iris and retina, and abnormal lacrimal duct. Craniofacial findings include asymmetry, notched nostrils, cleft lip and palate, and pointed chin. Almost 50% of affected patients have abnormal teeth mainly effecting enamel formation. Patients affected with FDH may also present syringocystadenoma papilliferum (Shaffer et al. 2009), a rare benign hamartomatous adnexal tumor originating from the apocrine or the eccrine sweat glands. Other FDH features include defects involving nails, hair, kidneys and the gastrointestinal system such as omphalocele and fused kidney. Approximately 15% of patients affected FDH present mental retardation.

FDH is an X-linked dominant condition caused by mutations in the PORCN gene. Approximately 90% of affected patients are females and 10% are males. 95% of female patients have a de novo mutation, and all live-born male patients are mosaic (Golz et al. 1992; Wang et al. 2007, Grzeschik et al. 2007; Sutton et al. 2013). One large deletion involving PORCN was documented in a patient affected with angioma serpiginosum (Houge et al. 2008), a rare benign congenital skin disorder characterized by nonpurpuric red punctate lesions following Blaschko lines.

PORCN protein coded by the PORCN gene is a putative O-acyltransferase enzyme that catalyzes cysteine N-palmitoylation and serine O-acylation in the endoplasmic reticulum. PORCN serves as a regulator of Wnt signal pathway during embryogenesis (Paller et al, 2007). To date, almost 100 unique pathogenic variants have been identified. They are: missense 22%, nonsense 24%, splicing 12%, small deletions and duplications 28% and gross deletions 14% (Human Gene Mutation Database; Lombardi et al. 2011). These pathogenic mutations were found in almost all coding exons, but not in exons 7 and 8 (Human Gene Mutation Database, Lombardi et al. 2011, Sutton et al. 2013). Three recurrent mutations were reported: c.370C>T (p.Arg124*); c.727C>T (p.Arg243*) and c.1094G>A (p.Arg365Gln) (Lombardi et al. 2011).

PORCN pathogenic variants were detected in all three male patients and 10 out of 15 female patients who were clinically diagnosed or suspected to have FDH (Wang et al. 2007). In another study, PORCN pathogenic and likely pathogenic variants were detected in 22 out of 53 unrelated clinically diagnosed FDH patients (Fernandes et al. 2010).

Large deletions account for ~14% pathogenic variants found in the PORCN gene (Human Gene Mutation Database; Lombardi et al. 2011 Fernandes et al. 2009; Sutton et al. 2013).

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