SLC2A9 and Hyperuricemia: A Locus-Wide Association Study To Identify Population-Specific Genetic Variants In New Zealand Māori and Pacific People

Hyperuricemia, pathologically defined as the presence of an elevated level of serum urate, is a prerequisite for gouty arthritis. The solute carrier family 2 member 9 (SLC2A9) gene that encodes a urate transporter tops the list of hyperuricemic genes. It is a key genetic determinant of serum urate levels and explains about 3% of urate variance. Gout is highly prevalent in the New Zealand Māori and other Polynesian populations. As an attempt to understand the reason for this increased prevalence, this study focused on the identification and characterisation of Polynesian-specific genetic variants within the SLC2A9 locus conferring susceptibility to hyperuricemia. The SLC2A9 locus was resequenced in 809 individuals (Polynesian, n = 440 and European, n = 369) comprising hyperuricemic cases and normouricemic controls. All Polynesians were from New Zealand while Europeans were from New Zealand and the United States. Association analysis was carried out to identify variants within the SLC2A9 locus that confer risk for hyperuricemia. Multiple adjusted logistic regression analysis was carried out using R version 3.4.1. A number of data visualization techniques and variant annotation tools were used to interpret and represent data and variant annotations. A total of 3963 variants was identified within the locus, of which 25 and 53 variants displayed nominal significance (p-value ≤ 0.05) with hyperuricemia in the East and West Polynesians, respectively. These significant signals were further analysed. Five variants were chosen for replication via genotyping (VAR_CHR4_9914056, rs373311989, VAR_CHR4_9452283, VAR_CHR4_10160679 and VAR_CHR4_10457448). The A allele of VAR_CHR4_9914056, located in intron 7 of the SLC2A9 gene, was found to be associated with hyperuricemia in the East Polynesians in the Discovery Cohort (adjusted OR = 28.30, POR = 0.003) and the association was successfully replicated in the larger independent Replication Cohort, although with a relatively smaller effect size (adjusted OR = 2.93, POR = 0.004). The variants prioritized for replication were also tested for the association with gout in Polynesians. The A allele of the intergenic variant, VAR_CHR4_10160679, showed a significant protective association with gout both during discovery (adjusted OR = 0.04, POR = 0.03) and replication (adjusted OR = 0.32, POR = 0.01) in West Polynesians. The region containing this variant (4:10120364 – 4:10494666) displayed variation in the haplotype structure in Polynesians compared to Europeans, as revealed by haplotype analysis and visualization. This research was conducted to provide a greater insight into the genetic causes of gout and understand the reason for the higher prevalence of hyperuricemia in Polynesians. The work signifies the usefulness of targeted resequencing, especially in a bespoke fashion, in studying the genetic basis of a trait/disease that is highly prevalent in a particular population and further evinces the association of non-coding variants in the SLC2A9 locus, mapping to the human 4p16.1 chromosomal region, with hyperuricemia and gout in Polynesians. The study also demonstrates the utility of data visualization tools and techniques in exploratory big data analysis. The identification of the Polynesian-specific hyperuricemia-associated variant can be applied in precision medicine and public health genomics to improve health outcomes for the target population

Intragenic Deletions in FLNB Are Part of the Mutational Spectrum Causing Spondylocarpotarsal Synostosis Syndrome

Spondylocarpotarsal synostosis syndrome (SCT) is characterized by vertebral fusions, a disproportionately short stature, and synostosis of carpal and tarsal bones. Pathogenic variants in FLNB, MYH3, and possibly in RFLNA, have been reported to be responsible for this condition. Here, we present two unrelated individuals presenting with features typical of SCT in which Sanger sequencing combined with whole genome sequencing identified novel, homozygous intragenic deletions in FLNB (c.1346-1372_1941+389del and c.3127-353_4223-1836del). Both deletions remove several consecutive exons and are predicted to result in a frameshift. To our knowledge, this is the first time that large structural variants in FLNB have been reported in SCT, and thus our findings add to the classes of variation that can lead to this disorder. These cases highlight the need for copy number sensitive methods to be utilized in order to be comprehensive in the search for a molecular diagnosis in individuals with a clinical diagnosis of SCT

Deletion of Exon 1 in AMER1 in Osteopathia Striata with Cranial Sclerosis

Osteopathia striata with cranial sclerosis (OSCS) is an X-linked dominant condition characterised by metaphyseal striations, macrocephaly, cleft palate, and developmental delay in affected females. Males have a more severe phenotype with multi-organ malformations, and rarely survive. To date, only frameshift and nonsense variants in exon 2, the single coding exon of AMER1, or whole gene deletions have been reported to cause OSCS. In this study, we describe two families with phenotypic features typical of OSCS. Exome sequencing and multiplex ligation-dependent probe amplification (MLPA) did not identify pathogenic variants in AMER1. Therefore, genome sequencing was employed which identified two deletions containing the non-coding exon 1 of AMER1 in the families. These families highlight the importance of considering variants or deletions of upstream non-coding exons in conditions such as OSCS, noting that often such exons are not captured on probe or enrichment-based platforms because of their high G/C content

Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism

ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder