Universität zu Köln

Abdel-Salam, Ghada M. H., Abdel-Hamid, Mohamed S., Sayed, Inas S. M., Zechner, Ulrich and Bolz, Hanno Joern (2022). OTUD6B-associated intellectual disability: novel variants and genetic exclusion of retinal degeneration as part of a refined phenotype. J. Hum. Genet., 67 (1). S. 55 - 65. LONDON: SPRINGERNATURE. ISSN 1435-232X

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Abstract

Biallelic pathogenic variants of OTUD6B have recently been described to cause intellectual disability (ID) with seizures. Here, we report the clinical and molecular characterization of five additional patients (from two unrelated Egyptian families) with ID due to homozygous OTUD6B variants. In Family I, the two affected brothers had additional retinal degeneration, a symptom not yet reported in OTUD6B-related ID. Whole-exome sequencing (WES) identified a novel nonsense variant in OTUD6B (c.271C>T, p.(Gln91Ter)), but also a nonsense variant in RP1L1 (c.5959C>T, p.(Gln1987Ter)), all in homozygous state. Biallelic pathogenic variants in RP1L1 cause autosomal recessive retinitis pigmentosa type 88 (RP88). Thus, RP1L1 dysfunction likely accounts for the visual phenotype in this family with two simultaneous autosomal recessive disorders. In Family II, targeted sequencing revealed a novel homozygous missense variant (c.767G>T, p.(Gly256Val)), confirming the clinically suspected OTUD6B-related ID. Consistent with the clinical variability in previously reported OTUD6B patients, our patients showed inter- and intrafamilial differences with regard to the clinical and brain imaging findings. Interestingly, various orodental features were present including macrodontia, dental crowding, abnormally shaped teeth, and thick alveolar ridges. Broad distal phalanges (especially the thumbs and halluces) with prominent interphalangeal joints and fetal pads were recognized in all patients and hence considered pathognomonic. Our study extends the spectrum of the OTUD6B-associated phenotype. Retinal degeneration, albeit present in both patients from Family I, was shown to be unrelated to OTUD6B, demonstrating the need for in-depth analysis of WES data in consanguineous families to uncover simultaneous autosomal recessive disorders.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Abdel-Salam, Ghada M. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Abdel-Hamid, Mohamed S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sayed, Inas S. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zechner, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Bolz, Hanno Joern UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-586550
DOI:	10.1038/s10038-021-00966-2
Journal or Publication Title:	J. Hum. Genet.
Volume:	67
Number:	1
Page Range:	S. 55 - 65
Date:	2022
Publisher:	SPRINGERNATURE
Place of Publication:	LONDON
ISSN:	1435-232X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MUTATIONS; RP1L1 Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/58655