Intellectual disabilityGene: CXorf56
Verkerk et al (2018 - PMID: 29374277) reported on a three-generation family with five males and one female presenting mild non-syndromic ID. Segregation was compatible with X-linked inheritance.
Multipoint linkage analysis with XL microsatellite markers demonstrated a linkage peak at Xq23-24 with LOD score of 3.3. Haplotype analysis and utilization of additional STR markers allowed narrowing to a region of 7.6 Mb containing 92 genes.
WGS in 3 affected males (spanning 3 generations) and 1 unaffected male and application of relevant filters for rare protein affecting variants within this region - present only in affected but absent in the unaffected individual - suggested a CXorf56 frameshift variant in exon 2 [NM_022101.3:c.159_160insTA / p.(Asp54*)] as the only relevant for this phenotype.
Sanger sequencing was performed for 25 family members with all 5 affected males and 1 affected female harboring this insertion and 8 unaffected females (also) shown to be carriers.
X-chromosome inactivation studies demonstrated that unaffected females had skewed inactivation (76-93%) of the variant allele, while the single affected female did not have a skewed XCI pattern (54%).
In EBV-transformed lymphoblasts grown with/without cycloheximide, mRNA levels were shown to be significantly lower in the affected female compared to unaffected ones (and corrected upon treatment with cycloheximide). mRNA levels were also significantly lower in cell lines from an affected male, with expression showing significant increase after treatment with cycloheximide. These results confirmed that nonsense-mediated decay applies.
The variant was absent from ExAC (where CXorf56 has a pLI of 0.93) and 188 healthy Dutch individuals.
The function of CXorf56 is not known. The gene appears to be expressed in brain and a (broad) range of other tissues [ https://gtexportal.org/home/gene/CXORF56 ].
Immunostaining in 8-week old murine brain, showed that the protein is present in the nucleus and cell soma of most neurons in brain cortex and cerebellum. Upon transfection of human CXorf56 cDNA in mouse primary hippocampal neurons, the protein localized in the nucleus, dendrites (co-localizing with Map2) and dendritic spines. As the authors note, the latter may suggest a role in synaptic function.
Overexpression in HEK293T cells demonstrated predominantly nuclear localization.
Mouse : Based on MGI (and an article by Cox et al. - PMID: 20548051 / both cited by the authors) male chimeras hemizygous for a gene trapped allele have abnormal midbrain-hindbrain boundary morphology, decreased forebrain size, while a subset hemizygous for a different gene trapped allele show growth delay [ http://www.informatics.jax.org/marker/MGI:1924894 ].
Rocha et al (2019 - PMID: 31822863) report on 9 affected individuals with mild to severe ID belonging to 3 unrelated families. Additional features in this cohort - observed in some - included abnormal reflexes, fine tremor, seizures (in 3), abnormal gait, etc.
In the 1st family, 3 males presented with (severe/severe/moderate) ID and 2 females with mild ID. Following a normal CMA and FMR1 testing, trio plus exome sequencing revealed a CXorf56 in-frame deletion [NM_022101.3:c.498_503del / p.(Glu167_Glu168del)]. Sanger sequencing in 9 members, confirmed presence of the variant in one unaffected mother, all her affected sons (2) and daughers(2) and an affected grandson and absence in 2 remaining unaffected daughters. Skewing of XCI was seen in blood cells from affected females (97 and 83%) while the unaffected mother had complete inactivation of the carrier X-chromosome. The authors commented that even minor reductions in CXorf56 (suggested by XCI in affected females) may be detrimental and/or that inactivation for this gene may be different than that of AR gene (which was studied instead) or in other tissues.
In family 2, an affected mother (with learning difficulties) and her 2 sons - the most severely affected presenting moderate ID - harbored a frameshift variant [c.303_304delCTinsACCC / p.(Phe101Leufs*20)].
A male with ID belonging to a 3rd family, for which no further information was available, was found to harbor the c.498_503del variant (also discussed above) as a de novo event.
It has been commented that individuals with Xq24 deletions spanning CXorf56 present with ID, although (all) such deletions reported in the literature also span the neighboring UBE2A gene, associated with Mental retardation, X-linked syndromic, Nascimento-type (MIM #300860).
In OMIM, the CXorf56-related phenotype is ?Mental retardation, X-linked 107 (# 301013), based only on the report by Verkerk et al.
This gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc).
Overall, CXorf56 can be considered for inclusion in the ID panel either with amber (function of the gene unknown, skewed XCI also in affected females in the 2nd reference) or with green rating (several individuals from 4 families, compatible segregation studies and females presenting a milder phenotype than males or unaffected, LOD score in the 1st report, studies confirming lower mRNA levels and NMD, gene expressed in human brain, expression in mouse brain cortex and cerebellum, evidence from transfection studies in mouse hippocampal neurons).
[Note : penetrance was here set to unknown / It was complete for males, incomplete for females].
Sources: Literature, Radboud University Medical Center, Nijmegen
Created: 23 Dec 2019, 10:26 p.m.
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
?Mental retardation, X-linked 107, 301013
gene: CXorf56 was added gene: CXorf56 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: CXorf56 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: CXorf56 were set to 29374277; 31822863 Phenotypes for gene: CXorf56 were set to ?Mental retardation, X-linked 107, 301013 Penetrance for gene: CXorf56 were set to unknown Review for gene: CXorf56 was set to AMBER