Biallelic variants inDNA2cause poikiloderma with congenital cataracts and severe growth failure reminiscent of Rothmund-Thomson syndrome

Abstract

Rothmund-Thomson syndrome (RTS) is a rare, heterogeneous autosomal recessive genodermatosis, with poikiloderma as its hallmark. It is classified into two types: type I, with biallelic variants inANAPC1and juvenile cataracts, and type II, with biallelic variants inRECQL4, increased cancer risk and no cataracts. We report on six Brazilian probands and two siblings of Swiss/Portuguese ancestry presenting with severe short stature, widespread poikiloderma and congenital ocular anomalies. Genomic and functional analysis revealed compound heterozygosis for a deep intronic splicing variant in trans with loss of function variants inDNA2, with reduction of the protein levels and impaired DNA double-strand break repair. The intronic variant is shared by all patients, as well as the Portuguese father of the European siblings, indicating a probable founder effect. Biallelic variants inDNA2were previously associated with microcephalic osteodysplastic primordial dwarfism. Although the individuals reported here present a similar growth pattern, the presence of poikiloderma and ocular anomalies is unique. Thus, we have broadened the phenotypical spectrum ofDNA2mutations, incorporating clinical characteristics of RTS. Although a clear genotype–phenotype correlation cannot be definitively established at this moment, we speculate that the residual activity of the splicing variant allele could be responsible for the distinct manifestations ofDNA2-related syndromes.

Rothmund-Thomson syndrome, a disorder far from solved

“…Our group was responsible for the discovery of another gene related to RTS (Di Lazzaro Filho et al, 2023). By the analyses of an admixed cohort, a specific cluster of patients displayed clinical symptoms reminiscent of RTS, but with a distinct genetic basis.…”

“…Although two out of four individuals reported by Tarnauskaitė et al (2019) presented sparse hair, no additional findings compatible with the diagnosis of RTS were reported. Therefore, these individuals were not included in Table 1 along with the individuals reported by our group with characteristics reminiscent of RTS (Di Lazzaro Filho et al, 2023). The mechanisms explaining the phenotypic differences between DNA2-related RTS and DNA2-related MPD remain to be determined.…”

“…Perhaps the most well-established role of DNA2, at least in human cells, is its involvement in the repair of DSBs via homologous recombination (Zhu et al, 2008;Di Lazzaro Filho et al, 2023). In this process, the initial resection of the DSB regions is performed by the MRN complex, which degrades only a few nucleotides (short resection) (Zhu et al, 2008), activated by the CtIP protein.…”