@article {204, title = {Challenges and solutions for gene identification in the presence of familial locus heterogeneity.}, journal = {Eur J Hum Genet}, volume = {23}, year = {2015}, month = {2015 Sep}, pages = {1207-15}, abstract = {

Next-generation sequencing (NGS) of exomes and genomes has accelerated the identification of genes involved in Mendelian phenotypes. However, many NGS studies fall short of identifying causal variants, with estimates for success rates as low as 25\% for uncovering the pathological variant underlying disease etiology. An important reason for such failures is familial locus heterogeneity, where within a single pedigree causal variants in two or more genes underlie Mendelian trait etiology. As examples of intra- and inter-sibship familial locus heterogeneity, we present 10 consanguineous Pakistani families segregating hearing impairment due to homozygous variants in two different hearing impairment genes and a European-American pedigree in which hearing impairment is caused by four variants in three different genes. We have identified 41 additional pedigrees with syndromic and nonsyndromic hearing impairment for which a single previously reported hearing impairment gene has been identified but only segregates with the phenotype in a subset of affected pedigree members. We estimate that locus heterogeneity occurs in 15.3\% (95\% confidence interval: 11.9\%, 19.9\%) of the families in our collection. We demonstrate novel approaches to apply linkage analysis and homozygosity mapping (for autosomal recessive consanguineous pedigrees), which can be used to detect locus heterogeneity using either NGS or SNP array data. Results from linkage analysis and homozygosity mapping can also be used to group sibships or individuals most likely to be segregating the same causal variants and thereby increase the success rate of gene identification.

}, keywords = {Asian Continental Ancestry Group, Calcium-Binding Proteins, Chromosome Mapping, Connexin 26, Connexins, Consanguinity, European Continental Ancestry Group, Female, Genes, Recessive, Genetic Heterogeneity, Genetic Linkage, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genotype, Hearing Loss, Hepatocyte Growth Factor, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Male, Membrane Transport Proteins, Mutation, Pedigree, Phenotype, Sulfate Transporters}, issn = {1476-5438}, doi = {10.1038/ejhg.2014.266}, author = {Rehman, Atteeq U and Santos-Cortez, Regie Lyn P and Drummond, Meghan C and Shahzad, Mohsin and Lee, Kwanghyuk and Morell, Robert J and Ansar, Muhammad and Jan, Abid and Wang, Xin and Aziz, Abdul and Riazuddin, Saima and Smith, Joshua D and Wang, Gao T and Ahmed, Zubair M and Gul, Khitab and Shearer, A Eliot and Smith, Richard J H and Shendure, Jay and Bamshad, Michael J and Nickerson, Deborah A and Hinnant, John and Khan, Shaheen N and Fisher, Rachel A and Ahmad, Wasim and Friderici, Karen H and Riazuddin, Sheikh and Friedman, Thomas B and Wilch, Ellen S and Leal, Suzanne M} } @article {134, title = {Expanding the Molecular and Clinical Phenotype of SSR4-CDG.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Nov}, pages = {1048-51}, abstract = {

Congenital disorders of glycosylation (CDG) are a group of mostly autosomal recessive disorders primarily characterized by neurological abnormalities. Recently, we described a single CDG patient with a de novo mutation in the X-linked gene, Signal Sequence Receptor 4 (SSR4). We performed whole-exome sequencing to identify causal variants in several affected individuals who had either an undifferentiated neurological disorder or unsolved CDG of unknown etiology based on abnormal transferrin glycosylation. We now report eight affected males with either de novo (4) or inherited (4) loss of function mutations in SSR4. Western blot analysis revealed that the mutations caused a complete loss of SSR4 protein. In nearly all cases, the abnormal glycosylation of serum transferrin was only slightly above the accepted normal cutoff range.

}, keywords = {Calcium-Binding Proteins, Congenital Disorders of Glycosylation, DNA Mutational Analysis, Exome, Gene Order, Genes, X-Linked, Genetic Loci, Humans, Male, Membrane Glycoproteins, Mutation, Phenotype, Receptors, Cytoplasmic and Nuclear, Receptors, Peptide}, issn = {1098-1004}, doi = {10.1002/humu.22856}, author = {Ng, Bobby G and Raymond, Kimiyo and Kircher, Martin and Buckingham, Kati J and Wood, Tim and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J and Wong, Jonathan T S and Monteiro, Fabiola Paoli and Graham, Brett H and Jackson, Sheryl and Sparkes, Rebecca and Scheuerle, Angela E and Cathey, Sara and Kok, Fernando and Gibson, James B and Freeze, Hudson H} } @article {224, title = {Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Oct}, pages = {1135-1139}, abstract = {

Upon detection of pathogen-associated molecular patterns, innate immune receptors initiate inflammatory responses. These receptors include cytoplasmic NOD-like receptors (NLRs) whose stimulation recruits and proteolytically activates caspase-1 within the inflammasome, a multiprotein complex. Caspase-1 mediates the production of interleukin-1 family cytokines (IL1FCs), leading to fever and inflammatory cell death (pyroptosis). Mutations that constitutively activate these pathways underlie several autoinflammatory diseases with diverse clinical features. We describe a family with a previously unreported syndrome featuring neonatal-onset enterocolitis, periodic fever, and fatal or near-fatal episodes of autoinflammation. We show that the disease is caused by a de novo gain-of-function mutation in NLRC4 encoding a p.Val341Ala substitution in the HD1 domain of the protein that cosegregates with disease. Mutant NLRC4 causes constitutive IL1FC production and macrophage cell death. Infected macrophages from affected individuals are polarized toward pyroptosis and exhibit abnormal staining for inflammasome components. These findings identify and describe the cause of a life-threatening but treatable autoinflammatory disease that underscores the divergent roles of the NLRC4 inflammasome.

}, keywords = {Calcium-Binding Proteins, CARD Signaling Adaptor Proteins, Enterocolitis, Exome, Family Health, Fatal Outcome, Female, Humans, Inflammation, Male, Mutation, Missense, Pedigree, Sequence Analysis, DNA, Syndrome}, issn = {1546-1718}, doi = {10.1038/ng.3066}, author = {Romberg, Neil and Al Moussawi, Khatoun and Nelson-Williams, Carol and Stiegler, Amy L and Loring, Erin and Choi, Murim and Overton, John and Meffre, Eric and Khokha, Mustafa K and Huttner, Anita J and West, Brian and Podoltsev, Nikolai A and Boggon, Titus J and Kazmierczak, Barbara I and Lifton, Richard P} } @article {283, title = {A new congenital disorder of glycosylation caused by a mutation in SSR4, the signal sequence receptor 4 protein of the TRAP complex.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Mar 15}, pages = {1602-5}, abstract = {

Nearly 50 congenital disorders of glycosylation (CDG) are known, but many patients biochemically diagnosed with CDG do not have mutations in known genes. Here, we describe a 16-year-old male who was born with microcephaly, developed intellectual disability, gastroesophageal reflux and a seizure disorder. We identified a de novo variant in the X-linked SSR4 gene which encodes a protein of the heterotetrameric translocon-associated protein (TRAP) complex. The c.316delT causes a p.F106Sfs*53 in SSR4 and also reduces expression of other TRAP complex proteins. The glycosylation marker Glyc-ER-GFP was used to confirm the underglycosylation in fibroblasts from the patient. Overexpression of the wild-type SSR4 allele partially restores glycosylation of the marker and of the other members of the TRAP complex. This is the first evidence that the TRAP complex, which binds to the oligosaccharyltransferase complex, is directly involved in N-glycosylation.

}, keywords = {Adolescent, Calcium-Binding Proteins, Cells, Cultured, Chromosomes, Human, X, Congenital Disorders of Glycosylation, Glycosylation, Humans, Male, Membrane Glycoproteins, Point Mutation, Receptors, Cytoplasmic and Nuclear, Receptors, Peptide}, issn = {1460-2083}, doi = {10.1093/hmg/ddt550}, author = {Losfeld, Marie Estelle and Ng, Bobby G and Kircher, Martin and Buckingham, Kati J and Turner, Emily H and Eroshkin, Alexey and Smith, Joshua D and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J and Freeze, Hudson H} }