Facial Dysostosis Related Disorders Panel

Facial dysostosis is a group of congenital craniofacial anomalies caused by abnormal development of the first and second pharyngeal arches during embryogenesis. This test combines four smaller panels which cover following disorders:

1: Craniosynostosis and Related Disorders: Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia, Crouzon syndrome, Apert syndrome, CATSHL syndrome, Muenke syndrome, Pfeiffer syndrome, Osteoglophonic dysplasia, Jackson-Weiss syndrome, Hartsfield syndrome, LADD syndrome, Saethre-Chotzen syndrome, and Bent bone dysplasia syndrome.

2: Treacher Collins syndrome, Mandibulofacial Dysostosis/, Miller syndrome and Acrofacial dysostosis, Nager type

3: Cornelia de Lange Syndrome

4: Rubinstein-Taybi syndrome and Floating-Harbor Syndrome

This NextGen test analyzes multiple genes involved in Facial dysostosis related disorders as described in the clinical section.

Craniosynostosis and Related Disorders: FGFR1, FGFR2, FGFR3, TWIST1 and TCF12. These disorders are mainly inherited in an autosomal dominant manner, except for FGFR3-related CATSHL syndrome and FGFR1-relared Hartsfield syndrome, which can be inherited either in an autosomal dominant manner (mainly) or autosomal recessive manner. There is at least one reported autosomal recessive FGFR3-related CATSHL family and two reported FGFR1-related Hartsfield syndrome cases, respectively (Simonis et al. 2013; Makrythanasis et al. 2014).

Treacher Collins Syndrome: TCOF1, POLR1C, POLR1D. TCOF1-related Treacher Collins Syndrome is inherited in an autosomal dominant manner, while POLR1C-related Treacher Collins Syndrome is inherited in autosomal recessive manner. POLR1D related Treacher Collins Syndrome is mainly inherited in an autosomal dominant manner, except for two reported cases showed autosomal recessive inheritance.

Mandibulofacial Dysostosis: EFTUD2. Autosomal dominant.

Miller Syndrome: DHODH. Autosomal recessive.

Acrofacial dysostosis, Nager type: SF3B4. Autosomal dominant

Cornelia de Lange Syndrome (CdLS): NIPBL, SMC3, SMC1A, RAD21 and HDAC8. NIPBL, SMC3, and RAD21-related CdLS are inherited in autosomal dominant manner. SMC1A-related CdLSis inherited in an X-linked dominant manner (Deardorff et al. 2007). HDAC8-related CdLS is inherited in an X-linked manner, some HDAC8 heterozygous female carriers can be affected due to random X-inactivation (Deardorff et al. 2012).

Rubinstein-Taybi Syndrome: CREBBP and EP300. Autosomal dominant.

Floating-Harbor Syndrome: SRCAP. Autosomal dominant.

See individual gene test descriptions for information on clinical features of these disorders and molecular biology of gene products.

Craniosynostosis and Related Disorders:

~61% (111/182) of 182 Spanish craniosynostosis probands harbor a pathogenic variant in one of the FGFR2, FGFR3, TWIST1 and TCF12 genes. Pathogenic variants in FGFR2, FGFR3, TWIST and TCF12 account for 36%, 16%, 8% and 3% of pathogenic variants identified in this study, respectively (Paumard-Hernández et al. 2014).

TCF12 explains 32% and 10% of patients affected with bilateral and unilateral Craniosynostosis, respectively (Sharma et al. 2013).

One study reported that six unique FGFR1 pathogenic missense variants were found in seven unrelated patients affected with Hartsfield syndrome (Simonis et al. 2013). FGFR1 explains 5% of Pfeiffer syndrome type 1 cases (Robin et al. 2011).

Treacher Collins syndrome, Mandibulofacial Dysostosis/, Miller syndrome and Acrofacial dysostosis, Nager type:

TCOF1 pathogenic variants were found in ~70% of clinical diagnosed TCS cases, and large deletions are ~5% of reported TCOF1 pathogenic variants (Bowman et al. 2012; Katsanis and Jabs 2012).

POLR1D pathogenic variants were identified in 20 out of 242 (8%) unrelated TCS patients who were negative for TCOF1 variants. To date, only one large deletion has been reported (Dauwerse et al. 2010).

POLR1C pathogenic variants were identified in 3 out of 242 (~1%) unrelated patients with TCS or TCS phenotypic spectrum, who were negative for TCOF1 variants (Dauwerse et al. 2010).

Sequencing may detect up to 85% of disease causing mutations in clinically diagnosed Mandibulofacial Dysostosis, Guion-Almeida Type cases. Large deletion/insertions involving EFTUD2 cause ~15% of cases, which cannot be identified by sequencing (Lines 2012; Gordon et al. 2012; Need et al. 2012; Human Gene Mutation Database).

Rainger et al (2012) identified compound heterozygous pathogenic variants in DHODH in three out of eight unrelated families with Miller syndrome (Rainger et al. 2012).

Bernier et al. (2012) identified 18 different heterozygous SF3B4 pathogenic variants in 20 (57%) of 35 families affected by Acrofacial dysostosis, Nager type. Analytical sensitivity should be high because almost all of the documented SF3B4 pathogenic variants are point mutations, and small deletion/insertions which are expected to be detected by direct sequencing of genomic DNA.

Rubinstein-Taybi syndrome and Floating-Harbor Syndrome:

Sequence analysis can detect CREBBP pathogenic variants in 40%-50% of Rubinstein-Taybi syndrome cases. Pathogenic variants in EP300 are identified in ~3%-8% of patients with Rubinstein–Taybi syndrome (Stevens 2014). 16p13.3 microdeletions (size ranging from 3.3kb to 3900kb) involving CREBBP were found 17 out of 83 patients with typical features of Rubinstein–Taybi syndrome using array CGH and quantitative multiplex fluorescent-PCR (Stef et al. 2007).

In one study, SRCAP pathogenic variants were found in 6 out of 9 patients with Floating-Harbor syndrome (Le Goff et al. 2013).

Cornelia de Lange Syndrome:

Over 70% of all CdLS patients harbor a pathogenic variant in one of the five known CdLS genes (Boyle et al. 2014). This test does not detect large deletions or duplications spanning one or more exons.

Only five documented pathogenic variants in FGFR2 are large deletions/insertions (Human Gene Mutation Database; Bochukova et al. 2009). To date, no gross deletions or duplications have been reported in FGFR3 (Human Gene Mutation Database). Intragenic NIPBL deletions and a duplication were identified in 13 (2.5%) out of 510 CdLS cases (12 deletions and 1 duplication) (Cheng et al. 2014). Large deletions and duplications account for 11% of reported SMC1A pathogenic variants (Gilissen et al. 2014; Baquero-Montoya et al. 2014). There are no reported large deletions or duplications in SMC3 (Human Gene Mutation Database).

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).