Stickler Syndrome Panel

Stickler syndrome (STL) is a multisystem disorder characterized by ocular, skeletal, orofacial and auditory defects with an estimated prevalence of 1:7,500-1:9,000 (Robin et al. 2017. PubMed ID: 20301479). Ocular defects include myopia, cataract, and retinal detachment. Hearing loss can be both conductive and sensorineural. Other features include midfacial underdevelopment and cleft palate and mild spondyloepiphyseal dysplasia and/or precocious arthritis (Robin et al. 2017. PubMed ID: 20301479).

Stickler syndrome Type I (STL1) is characterized by “membranous” congenital vitreous anomaly; Stickler syndrome Type II (STL2) is characterized by “beaded” congenital vitreous anomaly, Stickler syndrome (STL3) has craniofacial and joint abnormalities and hearing loss, but no ocular findings. Stickler syndrome Type IV and Type V have moderate-to-severe sensorineural hearing loss and moderate-to-high myopia with vitreoretinopathy (Baker et al. 2011. PubMed ID: 21671392). Stickler syndrome Type VI features moderate-to-severe sensorineural hearing loss, moderate-to-high myopia, and midface retrusion (Faletra et al. 2014. PubMed ID: 24273071). One study suggested that hearing loss (mostly mild to moderate) was found in ~60% of Stickler patients (Acke et al. 2012. PubMed ID: 23110709). Stickler syndrome was also found in 39 out of 141 newborns who were diagnosed with Pierre-Robin sequence (Thouvenin et al. 2013. PubMed ID: 23303695).

Other skeletal disorders have overlapping clinical features with Stickler syndrome, which cause difficulties in reaching a correct clinical diagnosis. Molecular diagnosis of the skeletal dysplasia subtypes is also complex because extensive genetic heterogeneity exists for each disorder (Warman et al. 2011. PubMed ID: 21438135; Mortier et al. 2019. PubMed ID: 31633310). Considering the clinical and genetic heterogeneity, a molecular testing approach that interrogates all known Stickler syndrome genes is highly recommended.

The inheritance patterns of Stickler syndrome can be autosomal dominant (AD) or autosomal recessive (AR) (Robin et al. 2017. PubMed ID: 20301479). COL2A1, COL11A1, and COL11A2 are the major genes associated with autosomal dominant Stickler syndrome, while COL9A1, COL9A2 and COL9A3 are responsible for autosomal recessive Stickler syndrome (Robin et al. 2017. PubMed ID: 20301479; Van Camp et al. 2006. PubMed ID: 16909383; Baker et al. 2011. PubMed ID: 21671392; Nikopoulos et al. 2011. PubMed ID: 21421862; Vijzelaar et al. 2013. PubMed ID: 23621912). The proportion of de novo causative variants in Sticker syndrome patients is currently unknown (Robin et al. 2017. PubMed ID: 20301479).

Only a few LOXL3 variants were reported in individuals with autosomal recessive Stickler syndrome (Alzahrani et al. 2015. PubMed ID: 25663169; Chan et al. 2019. PubMed ID: 30362103).

Pathogenic variants in LRP2 mainly cause Donnai–Barrow syndrome (DBS) (Longoni et al. 2018. PubMed ID: 20301732). Recently, an undocumented homozygous LRP2 variant was found in two sibs, from one Saudi consanguineous family, affected with a predominant eye phenotype similar to Stickler syndrome (Schrauwen et al. 2014. PubMed ID: 23992033). To date, only a few autosomal recessive Stickler syndrome cases have been reported.

Pathogenic variants in VCAN cause Wagner syndrome (WS) (Kloeckener-Gruissem. 2016. PubMed ID: 20301747). The overlapping clinical features in WS and Stickler syndrome are myopia, presenile cataract, vitreous degeneration, radial perivascular retinal degeneration, and tractional retinal detachments (Kloeckener-Gruissem. 2016. PubMed ID: 20301747).

Several variants in BMP4 were reported in patients with cleft lip/palate (Suzuki. 2009. PubMed ID: 19249007). One truncating variant was reported to segregate in a family with autosomal dominant Stickler syndrome and renal dysplasia (Nixon et al. 2019. PubMed ID: 30568244). Approximately 10 large deletion/duplications involving BMP4 were reported in patients with eye, brain, and limb defects, and other conditions (Human Gene Mutation Database).

To date, only two homozygous variants in GZF1 were found in two consanguineous families with Larsen Syndrome (Patel et al. 2017. PubMed ID: 28475863). Larsen syndrome overlaps several features with Stickler syndrome such as severe myopia and hearing loss.

Only a few variants in PLOD3 were reported in patients with autosomal recessive connective tissue disorder (Ewans et al. 2019. PubMed ID: 31129566).

See individual gene test descriptions for information on molecular biology of gene products and spectra of pathogenic variants.

Causative variants in COL2A1 and COL11A1 account for 80-90% and 10-20% of variants identified in autosomal dominant STL syndrome, respectively; causative variants in COL11A2 account for rare dominant cases. Causative variants in  COL2A1, COL9A1, COL9A2, COL9A3, LOXL3 and LRP2 have been found only in a few families affected with autosomal recessive inheritance of STL syndrome (Robin et al. 2017. PubMed ID: 20301479; Schrauwen et al. 2014. PubMed ID: 23992033; Alzahrani et al. 2015. PubMed ID: 25663169; Tham et al. 2015. PubMed ID: 25060605). Causative variants in VCAN were identified in ten out of twelve families diagnosed with VCAN-related vitreoretinopathy (Kloeckener-Gruissem. 2016. PubMed ID: 20301747). Only one BMP4 truncating variant was reported to segregate in a family with autosomal dominant Stickler syndrome and renal dysplasia (Nixon et al. 2019. PubMed ID: 30568244).

The sensitivity for large deletions and duplications in COL2A1, COL11A2, COL9A1, COL9A2, and COL9A3 is probably low, because only a few cases with large deletions and insertions involving these five genes have been reported (van der Hout et al. 2002. PubMed ID: 12204008; Human Mutation Database). However, large deletions in COL11A1 were detected in six unrelated Stickler syndrome patients by MLPA methods (Vijzelaar et al. 2013. PubMed ID: 23621912).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).