Syndromic X-linked intellectual disability segregating with a missense variant in RLIM.
We describe a three-generation Norwegian family with a novel X-linked intellectual disability (XLID) syndrome characterized by subtle facial dysmorphism, autism and severe feeding problems. By exome sequencing we detected a rare missense variant (c.1067A>G, p.(Tyr356Cys)) in the RLIM gene, in two affected male second cousins. Sanger sequencing confirmed the presence of the variant in the four affected males (none of whom were siblings) and in three mothers available for testing. The variant was not present in 100 normal Norwegian controls, has not been reported in variant databases and is deleterious according to in silico prediction tools. The clinical phenotype and the variant co-segregate, yielding a LOD score of 3.0 for linkage to the shared region (36.09 Mb), which contains 242 genes. No other shared rare variants on the X chromosome were detected in the two affected exome-sequenced individuals, and all female carriers had an extremely skewed X-chromosome inactivation pattern. RLIM encodes RING zinc finger protein 12 (RNF12), an ubiquitin ligase that is essential for X inactivation in mice and that acts as a co-regulator of a range of transcription factors, particularly those containing a LIM homeodomain. Tyrosine in position 356 in RNF12 is located within a highly conserved domain essential for binding such transcription factors. Expression of RNF12 is widespread during embryogenesis, and is particularly high in the outer layers of the cerebral cortex. Functional studies are needed to prove a definite causal relationship between the variant and the phenotype. Subsequent reports may confirm a role for RLIM variants in patients with XLID.
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Elin
E
Tønne
Department of Clinical Science, University of Bergen, Bergen, Norway.
Rita
R
Holdhus
Department of Clinical Science, University of Bergen, Bergen, Norway.
Christine
C
Stansberg
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Asbjørg
A
Stray-Pedersen
Computational Biology Unit, University of Bergen, Bergen, Norway.
Kjell
K
Petersen
Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen, The Netherlands.
Han G
HG
Brunner
Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen, The Netherlands.
Christian
http://orcid.org/0000-0003-1693-9699
C
Gilissen
Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen, The Netherlands.
Alexander
A
Hoischen
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Trine
T
Prescott
Department of Clinical Science, University of Bergen, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
Vidar M
VM
Steen
Department of Clinical Science, University of Bergen, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
Torunn
T
Fiskerstrand
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D038901:X-Linked Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
C492370:RLIM protein, human; D044767:Ubiquitin-Protein Ligases