%0 Journal Article %J Am J Hum Genet %D 2016 %T Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome. %A Lindstrand, Anna %A Frangakis, Stephan %A Carvalho, Claudia M B %A Richardson, Ellen B %A McFadden, Kelsey A %A Willer, Jason R %A Pehlivan, Davut %A Liu, Pengfei %A Pediaditakis, Igor L %A Sabo, Aniko %A Lewis, Richard Alan %A Banin, Eyal %A Lupski, James R %A Davis, Erica E %A Katsanis, Nicholas %K Adolescent %K Adult %K Alleles %K Animals %K Bardet-Biedl Syndrome %K Child %K Child, Preschool %K Chromosome Breakpoints %K Cytoskeletal Proteins %K DNA Copy Number Variations %K Exons %K Female %K Gastrulation %K Genes, Recessive %K Humans %K Infant %K Male %K Mutation %K Pedigree %K Young Adult %K Zebrafish %K Zebrafish Proteins %X

Bardet-Biedl syndrome (BBS) is a defining ciliopathy, notable for extensive allelic and genetic heterogeneity, almost all of which has been identified through sequencing. Recent data have suggested that copy-number variants (CNVs) also contribute to BBS. We used a custom oligonucleotide array comparative genomic hybridization (aCGH) covering 20 genes that encode intraflagellar transport (IFT) components and 74 ciliopathy loci to screen 92 unrelated individuals with BBS, irrespective of their known mutational burden. We identified 17 individuals with exon-disruptive CNVs (18.5%), including 13 different deletions in eight BBS genes (BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, BBS7, BBS9, and NPHP1) and a deletion and a duplication in other ciliopathy-associated genes (ALMS1 and NPHP4, respectively). By contrast, we found a single heterozygous exon-disruptive event in a BBS-associated gene (BBS9) in 229 control subjects. Superimposing these data with resequencing revealed CNVs to (1) be sufficient to cause disease, (2) Mendelize heterozygous deleterious alleles, and (3) contribute oligogenic alleles by combining point mutations and exonic CNVs in multiple genes. Finally, we report a deletion and a splice site mutation in IFT74, inherited under a recessive paradigm, defining a candidate BBS locus. Our data suggest that CNVs contribute pathogenic alleles to a substantial fraction of BBS-affected individuals and highlight how either deletions or point mutations in discrete splice isoforms can induce hypomorphic mutations in genes otherwise intolerant to deleterious variation. Our data also suggest that CNV analyses and resequencing studies unbiased for previous mutational burden is necessary to delineate the complexity of disease architecture.

%B Am J Hum Genet %V 99 %P 318-36 %8 2016 Aug 04 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/27486776?dopt=Abstract %R 10.1016/j.ajhg.2015.04.023 %0 Journal Article %J Am J Hum Genet %D 2015 %T De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome. %A Burrage, Lindsay C %A Charng, Wu-Lin %A Eldomery, Mohammad K %A Willer, Jason R %A Davis, Erica E %A Lugtenberg, Dorien %A Zhu, Wenmiao %A Leduc, Magalie S %A Akdemir, Zeynep C %A Azamian, Mahshid %A Zapata, Gladys %A Hernandez, Patricia P %A Schoots, Jeroen %A de Munnik, Sonja A %A Roepman, Ronald %A Pearring, Jillian N %A Jhangiani, Shalini %A Katsanis, Nicholas %A Vissers, Lisenka E L M %A Brunner, Han G %A Beaudet, Arthur L %A Rosenfeld, Jill A %A Muzny, Donna M %A Gibbs, Richard A %A Eng, Christine M %A Xia, Fan %A Lalani, Seema R %A Lupski, James R %A Bongers, Ernie M H F %A Yang, Yaping %K Adolescent %K Amino Acid Sequence %K Base Sequence %K Cell Cycle %K Child, Preschool %K Congenital Microtia %K Dwarfism %K Exons %K Female %K Geminin %K Gene Expression %K Genes, Dominant %K Growth Disorders %K Heterozygote %K High-Throughput Nucleotide Sequencing %K Humans %K Inheritance Patterns %K Male %K Micrognathism %K Molecular Sequence Data %K Mutation %K Patella %K Pedigree %K Protein Stability %K Proteolysis %K RNA Splicing %K Sequence Alignment %X

Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5' end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6(∗)) and c.35_38delTCAA (p.Ile12Lysfs(∗)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5' end of the geminin protein. All three GMNN mutations identified alter sites 5' to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS.

%B Am J Hum Genet %V 97 %P 904-13 %8 2015 Dec 03 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/26637980?dopt=Abstract %R 10.1016/j.ajhg.2015.11.006 %0 Journal Article %J Am J Hum Genet %D 2013 %T TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities. %A Wiszniewski, Wojciech %A Hunter, Jill V %A Hanchard, Neil A %A Willer, Jason R %A Shaw, Chad %A Tian, Qi %A Illner, Anna %A Wang, Xueqing %A Cheung, Sau W %A Patel, Ankita %A Campbell, Ian M %A Gelowani, Violet %A Hixson, Patricia %A Ester, Audrey R %A Azamian, Mahshid S %A Potocki, Lorraine %A Zapata, Gladys %A Hernandez, Patricia P %A Ramocki, Melissa B %A Santos-Cortez, Regie L P %A Wang, Gao %A York, Michele K %A Justice, Monica J %A Chu, Zili D %A Bader, Patricia I %A Omo-Griffith, Lisa %A Madduri, Nirupama S %A Scharer, Gunter %A Crawford, Heather P %A Yanatatsaneejit, Pattamawadee %A Eifert, Anna %A Kerr, Jeffery %A Bacino, Carlos A %A Franklin, Adiaha I A %A Goin-Kochel, Robin P %A Simpson, Gayle %A Immken, Ladonna %A Haque, Muhammad E %A Stosic, Marija %A Williams, Misti D %A Morgan, Thomas M %A Pruthi, Sumit %A Omary, Reed %A Boyadjiev, Simeon A %A Win, Kay K %A Thida, Aye %A Hurles, Matthew %A Hibberd, Martin Lloyd %A Khor, Chiea Chuen %A Van Vinh Chau, Nguyen %A Gallagher, Thomas E %A Mutirangura, Apiwat %A Stankiewicz, Pawel %A Beaudet, Arthur L %A Maletic-Savatic, Mirjana %A Rosenfeld, Jill A %A Shaffer, Lisa G %A Davis, Erica E %A Belmont, John W %A Dunstan, Sarah %A Simmons, Cameron P %A Bonnen, Penelope E %A Leal, Suzanne M %A Katsanis, Nicholas %A Lupski, James R %A Lalani, Seema R %K Age of Onset %K Aging, Premature %K Asian People %K Base Sequence %K Brain %K Child %K Child, Preschool %K Chromosomes, Human, Pair 2 %K Exons %K Female %K Genetic Predisposition to Disease %K Humans %K Language Development Disorders %K Leukoencephalopathies %K Magnetic Resonance Imaging %K Male %K Molecular Sequence Data %K Pedigree %K Sequence Analysis, DNA %K Sequence Deletion %K Tetraspanins %X

White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ~70% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.

%B Am J Hum Genet %V 93 %P 197-210 %8 2013 Aug 08 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/23810381?dopt=Abstract %R 10.1016/j.ajhg.2013.05.027