Mental Retardation with Cerebellar Hypoplasia and Distinctive Facial Appearance via the OPHN1 Gene

X-linked mental retardation with cerebellar hypoplasia and distinctive facial appearance (OMIM 300486) is a clinically heterogeneous disorder with intrafamilial and interfamilial phenotypic variability (Zanni et al. Neurology 65:1364-1369, 2005). X-linked mental retardation with cerebellar hypoplasia and distinctive facial appearance is mainly characterized by moderate to severe mental retardation and cerebellar anomalies, particularly cerebellar vermis hypoplasia presented as isolated vermis hypoplasia and common facial features such as prominent supraorbital ridges, hypotelorism, deep-set eyes, long tubular nose, short philtrum, thin upper lip, and prominent chin (Billuart et al. Nature 392:923-926, 1998; Philip et al. J Med Genet 40:441-446, 2003; Zanni et al. 2005). Brain imaging (MRI) may also reveal cerebral atrophy, ventriculomegaly, and rarely hydrocephalus (Zanni et al. 2005). Other clinical findings such as tall stature, macrocephaly, hypotonia, developmental delay, seizures, oculomotor problems, language problems, and neurological and behavioral problems such as dysmetria, adiadochokinesia, hyperactivity, and anxiety have been occasionally reported (Philip et al. 2003; Zanni et al. 2005).

X-linked mental retardation with cerebellar hypoplasia is inherited as X-linked recessive disorder, where males are more severely affected than females. However heterozygous females may have mild cognitive impairments (Zanni et al. Neurology 65: 1364-1369, 2005). X-linked mental retardation with cerebellar hypoplasia is caused by variants in the oligophrenin-1 (OPHN1) gene (Billuart et al. Nature 392: 923-926, 1998). OPHN1 gene encodes the oligophrenin-1 protein, which contains a domain common in Rho-GTPase-activating proteins suggesting a role in cell migration and outgrowth of axons and dendrites, neuronal morphogenesis and synapse maturation (Billuart et al. 1998; Zanni et al 2005). A mix of nonsense, splice site, frameshift, and single- and multiple-exon deletion variants have been reported in the OPHN1 gene (Billuart et al. 1998; Philip et al. J Med Genet 40: 441-446, 2003; Bergmann et al. Brain 126:1537-1544, 2003, Chabrol et al. Am J Med Genet 138: 314-317, 2005).

OPHN1 variants were found in approximately 12% of patients with mental retardation with known cerebellar anomalies and in about 1% of X-linked mental retardation patients (Zanni et al. Neurology 65:1364-9, 2005).

This test provides full coverage of all coding exons of the OPHN1 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).