Project description:CDAGS Syndrome is a rare congenital disorder characterized by Craniosynostosis, Delayed closure of the fontanelles, cranial defects, clavicular hypoplasia, Anal and Genitourinary malformations, and Skin manifestations. We performed exome sequencing to identify the underlying molecular cause in five patients with CDAGS syndrome from four distinct families. Whole exome sequencing revealed rare variants that disrupt highly conserved nucleotides within the RNU12 gene. RNU12 encodes a small nuclear RNA that is a component of the minor spliceosome and is essential for minor intron splicing. Targeted sequencing confirmed allele segregation within the four families. All five patients in this cohort have a rare variant on one allele that either disrupts the secondary structure or the Sm binding site of the RNU12 snRNA. The variant on the other allele, shared among all five cases, alters a highly conserved nucleotide within the precursor U12 snRNA 3’ extension that is absent in 1440 unrelated healthy controls. All of the variants are either rare or absent from all searched public databases. Whole transcriptome sequencing analysis identified gene dysregulation and specific defects in intron retention in a subset of minor intron splicing. These findings provide evidence of the involvement of RNU12 in craniosynostosis, anal and genitourinary patterning and cutaneous disease.
Project description:Anophthalmia, microphthalmia and coloboma (AMC) comprise a spectrum of developmental eye disorders, accounting for approximately 20% of childhood visual impairment. While non-coding regulatory sequences are increasingly recognised as contributing to disease burden, characterising their impact on gene function and phenotype remains challenging. Furthermore, little is known of the nature and extent of their contribution to AMC phenotypes. We identified two families with variants in or near MAB21L2. The first proband, with microphthalmia and coloboma, had a likely pathogenic missense variant (c.338G>C; p.[Trp113Ser]), segregating within the family. The second individual, presenting with microphthalmia, had an ~113.5kb homozygous deletion 19.38kb upstream of MAB21L2. Modelling the deletion led to transient small lens and coloboma in zebrafish, and microphthalmia and coloboma in Xenopus tropicalis. Conservation analysis identified 15 non-genic conserved elements (CE) within the deleted region, while ChIP-seq data from mouse embryonic stem cells demonstrated one of these (CE14) binds OTX2, a protein with an established role in eye development. Targeted disruption of CE14 in Xenopus tropicalis recapitulated an ocular coloboma phenotype, supporting its role in eye development. Together, our data provides insights into regulatory mechanisms underlying eye development, and highlights the importance of non-coding sequences as a source of genetic diagnoses in AMC.
Project description:Comparison of mRNA accumulation in segregating doubled haploid barley lines ****[PLEXdb(http://www.plexdb.org) has submitted this series at GEO on behalf of the original contributor, . The equivalent experiment is BB21 at PLEXdb.]
Project description:Brisbane Systems Genetics Study comprises of a total of 862 individuals from 374 families. Families consist of combinations of both MZ and DZ twin pairs, their siblings and for 72 families their parents.