Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy.
Laura J GrangeJohn J ReynoldsFarid UllahBertrand IsidorRobert F ShearerXenia LatypovaRyan M BaxleyAntony W OliverAnil GaneshSophie L CookeSatpal S JhujhGavin S McNeeRobert HollingworthMartin R HiggsToyoaki NatsumeTahir N KhanGabriel Á Martos-MorenoSharon ChuppChristopher G MathewDavid A ParryMichael A SimpsonNahid NahavandiZafer YükselMojgan DrasdoAnja KronPetra VogtAnnemarie JonassonSaad Ahmed SethClaudia Gonzaga-JaureguiKarlla W BrigattiAlexander P A StegmannMasato T KanemakiDragana JosifovaYuri UchiyamaYukiko OhAkira MorimotoHitoshi OsakaZineb AmmousJesús ArgenteNaomichi MatsumotoConstance T R M StumpelAlexander Malcolm TaylorAndrew P JacksonAnja-Katrin BielinskyNiels MailandCedric Le CaignecErica E DavisGrant S StewartPublished in: Nature communications (2022)
Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.
Keyphrases
- dna repair
- copy number
- induced apoptosis
- zika virus
- intellectual disability
- dna damage
- genome wide
- cell cycle arrest
- single cell
- stem cells
- case report
- dna methylation
- oxidative stress
- endoplasmic reticulum stress
- blood brain barrier
- chronic kidney disease
- machine learning
- molecular dynamics
- gene expression
- electronic health record
- circulating tumor
- growth hormone
- bone marrow
- cell proliferation
- bioinformatics analysis
- data analysis