Biallelic variants in DNA2 cause poikiloderma with congenital cataracts and severe growth failure reminiscent of Rothmund-Thomson syndrome.

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 in ANAPC1 and juvenile cataracts, and type II, with biallelic variants in RECQL4, 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 in DNA2, 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 in DNA2 were 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 of DNA2 mutations, 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 of DNA2-related syndromes.

Pathogenic variants detected by RNA sequencing in Cornelia de Lange syndrome.

Recent studies suggest that transcript isoforms significantly overlap (approximately 60%) between brain tissue and Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs). Interestingly, 14 cohesion-related genes with variants that cause Cornelia de Lange Syndrome (CdLS) are highly expressed in the brain and LCLs. In this context, we first performed RNA sequencing of LCLs from 22 solved (with pathogenic variants) and 19 unsolved (with no confirmed variants) CdLS cases. Next, an RNA sequencing pipeline was developed using solved cases with two different methods: short variant analysis (for single-nucleotide and indel variants) and aberrant splicing detection analysis. Then, 19 unsolved cases were subsequently applied to our pipeline, and four pathogenic variants in NIPBL (one inframe deletion and three intronic variants) were newly identified. Two of three intronic variants were located at Alu elements in deep-intronic regions, creating cryptic exons. RNA sequencing with LCLs was useful for identifying hidden variants in exome-negative cases.

Novel CLTC variants cause new brain and kidney phenotypes.

Heterozygous variants in CLTC, which encode the clathrin heavy chain protein, cause neurodevelopmental delay of varying severity, and often accompanied by dysmorphic features, seizures, hypotonia, and ataxia. To date, 28 affected individuals with CLTC variants have been reported, although their phenotypes have not been fully elucidated. Here, we report three novel de novo CLTC (NM_001288653.1) variants in three individuals with previously unreported clinical symptoms: c.3662_3664del:p.(Leu1221del) in individual 1, c.2878T>C:p.(Trp960Arg) in individual 2, and c.2430+1G>T:p.(Glu769_Lys810del) in individual 3. Consistent with previous reports, individuals with missense or small in-frame variants were more severely affected. Unreported symptoms included a brain defect (cystic lesions along the lateral ventricles of the brain in individuals 1 and 3), kidney findings (high-echogenic kidneys in individual 1 and agenesis of the left kidney and right vesicoureteral reflux in individual 3), respiratory abnormality (recurrent pneumonia in individual 1), and abnormal hematological findings (anemia in individual 1 and pancytopenia in individual 3). Of note, individual 1 even exhibited prenatal abnormality (fetal growth restriction, cystic brain lesions, high-echogenic kidneys, and a heart defect), suggesting that CLTC variants should be considered when abnormal prenatal findings in multiple organs are detected.

Cerebellofaciodental syndrome in an adult patient: Expanding the phenotypic and natural history characteristics.

Cerebellofaciodental syndrome is characterized by facial dysmorphisms, intellectual disability, cerebellar hypoplasia, and dental anomalies. It is an autosomal-recessive condition described in 2015 caused by pathogenic variants in BRF1. Here, we report a Brazilian patient who faced a diagnostic challenge beginning at 11 months of age. Fortunately, whole-exome sequencing (WES) was performed, detecting the BRF1 variants NM_001519.3:c.1649delG:p.(Gly550Alafs*36) and c.421C>T:p.(Arg141Cys) in compound heterozygosity, thus finally achieving a diagnosis of cerebellofaciodental syndrome. The patient is currently 25 years old and is the oldest patient yet reported. The clinical report and a review of published cases are presented. Atlanto-occipital fusion, a reduced foramen magnum and basilar invagination leading to compression of the medulla-spinal cord transition are skeletal findings not reported in previous cases. The description of syndromes with dental findings shows that such anomalies can be an important clue to relevant differential diagnoses. The cooperation of groups from different international centers made possible the resolution of this and other cases and is one of the strategies to bring medical advances to developing countries, where many patients with rare diseases are difficult to diagnose definitively.