A novel truncating variant in ring finger protein 113A (RNF113A) confirms the association of this gene with X‐linked trichothiodystrophy

Abstract

We describe an 11‐year old boy with severe global developmental delays, failure to thrive and growth retardation, refractory seizures with recurrent status epilepticus, hypogammaglobulinemia, hypergonadotropic hypogonadism, and duodenal strictures. He had facial and skin findings compatible with trichothiodystrophy, including sparse and brittle hair, thin eyebrows, and dry skin. Exome sequencing showed a hemizygous, truncating variant in RNF113A, c.903_910delGCAGACCA, predicting p.(Gln302fs*12), that was inherited from his mother. Although his clinical features overlap closely with features described in the two previously reported male first cousins with RNF113A loss of function mutations, the duodenal strictures seen in this patient have not been reported. Interestingly, the patient's mother had short stature and 100% skewed X‐inactivation as seen in other obligate female carriers. A second male with developmental delays, microcephaly, seizures, ambiguous genitalia, and facial anomalies that included sparse and brittle hair, thin eyebrows and dry skin was recently reported to have c.897_898delTG, predicting p.(Cys299*) in RNF113A and we provide additional clinical details for this patient. This report further supports deleterious variants in RNF113A as a cause of a novel trichothiodystrophy syndrome.

The expanding spectrum of NFIB‐associated phenotypes in a diverse patient population—A report of two new patients

“…Targeted regions were sequenced using the Illumina HiSeq 2,500 sequencing system (v3 chemistry), with a minimum of 10× coverage in 99.8% of targeted exon regions and a mean depth of coverage of 122 reads. Details of the bioinformatics variant filtering pipelines have been published previously (Mendelsohn et al, 2020). Validation was performed with Sanger sequencing.…”

A condensate forming tether for lariat debranching enzyme is defective in non-photosensitive trichothiodystrophy

“…We recently characterized a link between alkylation damage responses and RNF113A , a gene associated with NP-TTD (Brickner et al, 2017; Corbett et al, 2015; Mendelsohn et al, 2020; Tessarech et al, 2020; Tsao et al, 2021). We were curious about the molecular mechanism of pathology associated with TTDN1 , which is the most commonly altered gene associated with repair-proficient TTD (Faghri et al ., 2008).…”

“…Determining a unified basis for how NP-TTD shares molecular pathology with photosensitive TTD has remained obscure due to the genetic heterogeneity of the disease. Mutations in TF II Eβ (Theil et al, 2017), aminoacyl-tRNA synthetases (Botta et al, 2021; Kuo et al, 2019; Theil et al, 2019), and the splicing protein RNF113A (Corbett et al ., 2015; Mendelsohn et al ., 2020; Tessarech et al ., 2020) have all been linked to NP-TTD. We reasoned that the molecular defect between the latter and TTDN1 may both be explained by a common spliceosomal defect; indeed, RNF113A joins the activated spliceosome just prior to the first transesterification step in splicing (Haselbach et al, 2018), and alterations in RNA Pol II elongation are seen upon loss of the ASCC complex, which is recruited downstream of RNF113A (Brickner et al ., 2017; Williamson et al, 2017).…”

Return of non-ACMG recommended incidental genetic findings to pediatric patients: considerations and opportunities from experiences in genomic sequencing

“…SouthSeq [18], KidsCanSeq, P 3 EGS [19], and COAGS are research studies aimed at determining the benefit of using genomic sequencing (ES/GS) in pediatric patients to identify genetic variation underlying disease etiology (Table 1). SouthSeq, KidsCanSeq, and P 3 EGS are funded by the NIH as part of the CSER consortium.…”