NEW YORK (GenomeWeb) – Using a novel computational approach, researchers from the Deciphering Developmental Disorders Study have uncovered four new recessive developmental disorders.
The team led by the Wellcome Trust Sanger Center's Matthew Hurles analyzed the exomes of more than 4,000 families affected by diverse, rare, and genetically heterogeneous developmental disorders. Through a statistical approach that takes into consideration both the probability of sampling the observed genotypes and the observed phenotypes by chance, the team homed in on four new disorders, as it reported in Nature Genetics today.
"This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes," Hurles and his colleagues wrote in their paper.
The researchers analyzed the exomes of 4,125 families from the UK and Ireland with severe developmental disorders. While about a thousand of these families had possibly causative de novo mutations in a known disease-related gene, the remainder did not. To find candidate recessive genes in those families, the researchers sifted through their exomes to uncover all the biallelic rare protein-altering variants.
From this, they noted four variants — in LARP7, LINS, PIGT, and COL25A1 — that had previously been linked to recessive disorders in one or two families, albeit weakly, and now could be linked to additional families with similar phenotypes. They also confirmed apparently recessive forms of dominant disorders involving DEPDC5 and COL9A3.
To gauge the evidence supporting other candidate recessive genes, Hurles and his colleagues developed a statistical approach that relies on both Mendelian filtering and statistical assessments of the likelihood of sampling the observed genotypes in the general population and the phenotypic similarities of patients with recessive variants in the same candidate gene.
Through this, Hurles and his colleagues identified two genes with genome-wide significance, HACE1 and KIAA0586, neither of which had been previously linked to disease.
They found eight people from six families who were compound heterozygotes for two loss-of-function variants or a loss-of-function variant and a missense variant in KIAA0586. All of the patients shared the same p.Arg143Lysfs*4 loss-of-function variant.
Five of these six families, the researchers noted, had tentative diagnoses of Joubert syndrome.
KIAA0586 encodes TALPID3, a centrosomal protein that's needed for ciliogenesis and sonic hedgehog signaling. Genes linked with Joubert syndrome, the researchers noted, are also key to cilia function.
They further reported that mice homozygous for the null TALPID3 allele lacked cilia and were embryonic lethal. Because of that and as the affected people all shared the same loss-of-function variant, the researchers hypothesized that homozygosity for the allele in humans was also embryonic lethal and that the patients were compound heterozygotes for a null allele and a hypomorphic allele.
Meanwhile, they also uncovered three people from three families with biallelic rare loss-of-function variants in HACE1 and another family of three affected siblings who harbored a homozygous in-frame codon deletion in the gene.
HACE1, the researchers said, encodes a HECT domain-containing E3 ubiquitin ligase that is expressed in the brain. In mice, homozygous knockout of HACE3 is nearly almost always lethal before weaning, they reported.
Hurles and his colleagues also examined two genes that didn't quite meet genome-wide significance. Still, through co-segregation studies, additional clinical assessment, and animal models, they said there was compelling evidence that MMP21 and PRMT7 were linked to disease.
For instance, they identified two people and one fetus from two families who were compound heterozygous for different loss-of-function and missense variants in MMP21. These missense variants, the researchers added, were in close proximity to a highly conserved zinc-binding site, and both variants were predicted to influence enzymatic activity.
MMP21 is thought to function during embryonic development and modulate cell proliferation and migration. Mouse models with mutant MMP21, they reported, exhibited similar heart malformations as patients.
At the same time, the researchers uncovered six affected people from three families with compound heterozygous loss-of-function/loss-of-function variants or loss-of-function/functional variants in PRMT7.
PRMT7 encodes an arginine methyltransferase, the researchers noted, adding that protein modeling suggested that the observed missense variants were likely to be damaging. Mouse knockout models, they added, were sub-viable, and had smaller body sizes and weights.
Based on their characterizations of these four disorders, Hurles and his colleagues argued that their approach could uncover rare autosomal disorders. They pointed out, though, that their method relies on systematic genotype and phenotype data as well as phenotypic diversity among the families studied.
"Comprehensive discovery of all autosomal recessive causes of developmental disorders will require much larger datasets," Hurles and his colleagues said. "Inevitably, this will necessitate international collaboration and harmonizing of phenotypic data. "