OPHN1

Gene Facts

• HGNC Symbol: OPHN1 (HGNC:8148)
• HGNC Name: oligophrenin 1
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: MRX60
• Alias symbols: OPN1, ARHGAP41
• %HI: 35.46
• pLI: 1
• LOEUF: 0.16
• Cytoband: Xq12
• Genomic Coordinates:

  GRCh37/hg19:	chrX:67262186-67653337
  GRCh38/hg38:	chrX:68042344-68433841

• MANE Select Transcript: NM_002547.3 ENST00000355520.6
• Function: Stimulates GTP hydrolysis of members of the Rho family. Its action on RHOA activity and signaling is implicated in growth and stabilization of dendritic spines, and therefore in synaptic function. Critical for the stabilization of AMPA receptors at postsynaptic sites. Critical for the regulation of synaptic vesicle endocytosis at presynaptic terminals. Required for the localization of NR1D1 to dendrites, can suppress its repressor activity and protect it from proteasomal degradation (By similari... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-8280
• ClinGen Curation ID: CCID:007594
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 03/22/2023

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• X-linked intellectual disability-cerebellar hypoplasia syndrome

HI Evidence

• PUBMED: 16221952
  Zanni et al. (2005) reported loss of function variants in four families. In family A, a IVS2+2T>C splice site variant was found in a 6-year old boy with hypotonia, strabismus, nystagmus, developmental delay, intellectual disability, and ataxic gait. This variant led to skipping of exon 2 and a frameshift. No normal transcripts were detected. It was inherited from an unaffected mother. In family B, a deletion of exons 16 and 17 was found in six affected males whose features included intellectual disability, dysmorphic features, hypoplastic cerebellar vermis, and seizures. Carrier females were unaffected. In family C, four males with intellectual disability, dysmorphic features, and seizures were found to have a nonsense variant. Their mother was not available for testing. In family D, three males with intellectual disability, dysmorphic features, and cerebellar anomalies were found to have a nonsense variant, inherited from an unaffected mother.
• PUBMED: 20528889
  Al-Owain et al. (2011) reported a family with four boys and one girl with intellectual disability, seizures, cerebellar hypoplasia, and dysmorphic features with a 68 kb deletion of exons 7-15 of OPHN1. The girl had random X-inactivation. This deletion was inherited from an unaffected mother, but X-inactivation studies were not done for her. This paper also provides a review of all previous cases.
• PUBMED: 24817631
  Mignon-Ravix et al. (2014) reported a 4 kb deletion of exons 13–15 of OPHN1, causing a frameshift with a loss of 58 amino acids (pI370_F427delfsX24), in a male patient with global developmental delay and facial dysmorphism. Cerebral MRI showed cerebellar vermis hypoplasia with moderately dilated ventricles. Both parents were mildly disabled. Family history showed that the maternal grandmother had two half-brothers with intellectual disability. This study also revealed a deletion of MAP7D3 on Xq26.3, considered a potential candidate for intellectual disability. Paternal DNA was not available for study.
• PUBMED: 24105372
  Santos-Reboucas et al. (2014) described a three-generation Brazilian XLID family co-segregating a novel 21 kb intragenic deletion of OPHN1, resulting in-frame loss of exon 7 at the transcription level. This deletion was predicted to abolish 37 amino acids from the highly conserved N-terminal BAR domain of OPHN1. The affected males had intellectual disability and facial dysmorphism. Cranial MRI scans showed large lateral ventricles, vermis hypoplasia, and cystic dilatation of the cisterna magna in all affected males.
• PUBMED: 30534410
  Iida et al. (2019) reported a 13.5 kb maternally inherited deletion in OPHN1 ranging from exon 11-15 in a male patient with developmental delay. Brain CT and brain MRI suggested Dandy-Walker malformation (DWM). His maternal uncle was also affected with hydrocephalus,
• PUBMED: 32872024
  Boglis et al. (2020) detected a deletion of exon 21 of OPHN1 in a large family with several affected males (Family pedigree is shown in Figure 1), The clinical phenotype included mild developmental delay, behavioral disturbances, facial dysmorphism, pes planus, nystagmus, strabismus, epilepsy, and occipital arachnoid cyst.

• HI Evidence Comments: The oligophrenin 1 gene (OPHN1) is located on chromosome Xq12 and encodes a Rho-GTPase-activating protein (RhoGAP) involved in regulating the G-protein cycle. Pathogenic variants in OPHN1 have been identified in patients with X-linked intellectual disability, speech delay, seizures, strabismus, behavioral difficulties, facial dysmorphism, variably associated with cerebellar hypoplasia, and ventriculomegaly. In most of the cases so far reported, the identified genomic variants involve the region encoding the central RhoGAP domain of the oligophrenin-1 protein and are predicted to result in a complete loss of function. OPHN1 is highly expressed in fetal and adult brain, particularly in olfactory bulb, hippocampus, and cerebellum. Several animal studies showed the importance of OPHN1 in brain development in ophn1-defective mice, which displayed a reduction in newborn neurons number, dendritic spine immaturity, and alteration in synaptic function. Additional articles: PMID 17546640: Billuart et al. (1998) report a female patient with intellectual disability and a balanced t(X;12) with a breakpoint within intron 2 of OPHN1. No normal gene products were detected by RT-PCR. They then reported a family with four males with intellectual disability across three generations with a frameshift variant. Carrier females were intellectually normal. PMID 23416624 : Rocas et al. (2013) reported a female fetus diagnosed with cerebellar vermis hypoplasia without hemisphere abnormalities and a non-compressive expansion of the cisterna magna. The pregnancy was terminated. The array-CGH analysis of the fetus identified a 238 kb de novo deletion on chromosome Xp12, encompassing part of the OPHN1 gene. Microsatellite marker analysis showed that the deletion occurred on the paternal X chromosome. Further studies revealed a completely skewed pattern of X inactivation. PMID 31474318: Aldinger et al. (2019) identified a de novo 190.6 kb in-frame deletion in OPHN1 involving exons 3-15 in a male patient with a cerebellar malformation (Described in supplementary table 5). PMID 29510240: Moortgat et al. (2018) reported OPHN1 variants in 17 individuals from three unrelated families and one sporadic patient with intellectual disability, mild or no facial dysmorphism, and absence of cerebellar anomaly. Family A: Splice variant (c.384+3A > C, p.Val105_Lys128del) in four affected males and four affected females from a five-generation family. Family BL Nonsense variant (c.697C > T, p.(Gln233*)) in a male patient Family C: Missense variant (c.727C > T, p.(Arg243Trp) in five affected brothers Family D: Missense variant c.1235G > A, p. (Gly412Asp)) in an affected male PMID 33638601: Nuovo et al (2021) identified an in-frame c.116_127 deletion within the BAR domain segregated in two affected males and one affected female of a family presenting with a variable phenotype. The authors also described a missense c.2129C>T variant affecting the C-terminus domain in a male patient. The clinical features among all patients included developmental delay and intellectual disability of variable degrees, distinctive facial features, behavioral disorders, seizures, cerebellar hypoplasia, and ventriculomegaly. In addition to the papers referenced above, additional reports of loss of function variants resulting in intellectual disability, cerebellar anomalies, and consistent dysmorphic features can be found in PMIDs: 21796728, 18261018, 17304053, 12805098. See also patient 5 in Froyen et al (2007); PMID 17546640. In this family with affected males and OPHN1 deletion, the carrier mother was shown to have random X-inactivation. This suggests that X-inactivation status is not necessarily predictive of penetrance in carrier females.

NOTE

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity

TS Published Evidence

• PUBMED: 18512229
  Bedeschi et al. (2008) reported a male with an 800 kb duplication of OPHN1 and two other genes (YIPF6 & STARD8) inherited from his normal mother, who had skewed X-inactivation. The patient’s clinical features included intellectual disability, motor delays, seizures, scoliosis, asymmetry, and dysmorphic features that differed from those seen in patients with loss of function variants in OPHN1. A subsequent pregnancy was terminated at 21-week gestation due to hydrocephaly and cerebellar hypoplasia, but this duplication was not detected in that fetus.
• PUBMED: 22659343
  Isrie et al. (2012) detected a 790 kb duplication of Xq12 encompassing OPHN1, AR, and YIPF1 in a patient with intellectual disability and dysmorphic features.
• PUBMED: 28931914
  Chen et al. (2017) identified a 485 kb duplication of Xq12 involving OPHN1, YIPF1, and STARD8 in a patient with autism spectrum disorder.

• TS Evidence Comments: As described above, several duplications involving OPHN1 and additional genes have been reported. However, since focal duplications of OPHN1 alone have not been reported, the triplosensitivity score is 0.

NOTE

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.