CENPJ-Related Disorders via the CENPJ Gene

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder that results from hypoplasia of the cerebral cortex. The hallmark clinical feature of MCPH is a congenital decrease of the head circumference by at least three standard deviations below the population mean for age and sex that persists throughout the patient’s lifetime. Although MCPH has been initially characterized by severe microcephaly in the absence of other congenital anomalies (Jackson et al. Am J Hum Genet 63:541-546, 1998), structural anomalies of the central nervous system have been reported in several cases (Passemard et al. Neurology 73:962-969, 2009; Nicholas et al. Nat Genet 42:1010-1014, 2010; Yu et al. Nat Genet 42:1015-1020, 2010; Bacino et al. Am J Med Genet A 158A:622-625, 2012). Additional features may include a sloping forehead, various degrees of cognitive disabilities, seizures, congenital hearing loss, and short stature. Brain imaging findings include reduction of the cerebral cortical volume without gross brain malformations with simplification of the gyral cortical pattern, pachygyria with cortical thickening, hypoplasia, lissencephaly, and polymicrogyria (Jackson et al. Am J Hum Genet 71:136-142, 2002). In MCPH patients, microcephaly is detectable by the 32nd week of gestation and is apparent at birth (Woods et al. Am J Hum Genet 76:717-728, 2005). MCPH is panethnic. However, its incidence is variable and ranges from 1 in 30,000-250,000 live births (Passemard et al. GeneReviews, 2009, www.genetests.org) and is most elevated in populations where consanguineous marriages are broadly practiced (Bundey and Alam. Eur J Hum Genet 1:206-219, 1993).

Seckel syndrome (SCKL) is a rare disorder characterized by prenatal and postnatal growth delays. Most common clinical features include low birth weight, microcephaly, proportionate short stature, and varying degrees of mental retardation. Additional features include narrow face, large eyes, beak-like protrusion of the nose, malformed ears, small jaws, clinodactyly, dysplasia of the hips, and radial dislocation (Majewski and Goecke Am J Med Genet 12:7-21, 1982).

MCPH is a genetically heterogeneous disorder. To date, eight genes (ASPM, WDR62, MCPH1, CEP152, CENPJ, STIL, CDK5RAP2, and CEP135) have been implicated in the disorder (Bond et al. Nat Genet 32:316-320, 2002; Bilgüvar et al. Nature 467:207-210, 2010; Jackson. Am J Hum Genet 71:136–142, 2002; Guernsey et al. Am J Hum Genet 87:40-51, 2010; Bond et al. Nat Genet 37:353–355, 2005; Kumar et al. Am J Hum Genet 84:286–290, 2009; Hussain et al. Am J Hum Genet 90:871-878, 2012).

CENPJ variants account for less than 5% of cases with known variants (Passemard, GeneReviews. 2009). Four variants have been reported in MCPH cases. These include two missense variants and two small deletions that are predicted to result in truncated proteins. Variants have been reported in patients from various populations.

In addition to small head and various degrees of mental retardation, MCPH patients with CENPJ variants that have been reported to date presented with facial dysmorphism, developmental delay, joint stiffness, finger deformities, and seizures (Bond 2005, Gul et al. J Hum Genet 51:760-764, 2006, Darvish J Med Genet 47:823-828, 2010).

SCKL is a genetically heterogeneous disorder that is inherited in an autosomal recessive manner. Variants in five genes (ATR, CENPJ, CEP152, PCNT, and RBBP8) have been reported to be involved in SCKL (O'Driscoll et al. Nat Genet 33:497-501, 2003; Al-Dosari et al. J Med Genet 47:411-414, 2010; Kalay et al. Nat Genet 43:23-26, 2011; Griffith et al. Nat Genet 40:232-236, 2008; Qvist et al. PLoS Genet 7(10):e1002310, Epub 2011). Most variants are expected to result in truncated proteins. To date, only one splicing variant in the CENPJ gene was reported in one consanguineous family (Al-Dosari et al. J Med Genet 47:411-414, 2010).

The CENPJ gene encodes the centromeric protein J, which is involved in several functions including the maintenance of microsome integrity and spindle morphology.

This test will detect variants in less than 5% of patients with a clinical diagnosis of primary microcephaly (Passemard et al. GeneReviews, 2009, www.genetests.org). Variants in the CENPJ gene appear to be a rare cause of SCKL syndrome.

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