Abstract:
:New human mutations are thought to originate in germ cells, thus making a recurrence of the same mutation in a sibling exceedingly rare. However, increasing sensitivity of genomic technologies has anecdotally revealed mosaicism for mutations in somatic tissues of apparently healthy parents. Such somatically mosaic parents might also have germline mosaicism that can potentially cause unexpected intergenerational recurrences. Here, we show that somatic mosaicism for transmitted mutations among parents of children with simplex genetic disease is more common than currently appreciated. Using the sensitivity of individual-specific breakpoint PCR, we prospectively screened 100 families with children affected by genomic disorders due to rare deletion copy-number variants (CNVs) determined to be de novo by clinical analysis of parental DNA. Surprisingly, we identified four cases of low-level somatic mosaicism for the transmitted CNV in DNA isolated from parental blood. Integrated probabilistic modeling of gametogenesis developed in response to our observations predicts that mutations in parental blood increase recurrence risk substantially more than parental mutations confined to the germline. Moreover, despite the fact that maternally transmitted mutations are the minority of alleles, our model suggests that sexual dimorphisms in gametogenesis result in a greater proportion of somatically mosaic transmitting mothers who are thus at increased risk of recurrence. Therefore, somatic mosaicism together with sexual differences in gametogenesis might explain a considerable fraction of unexpected recurrences of X-linked recessive disease. Overall, our results underscore an important role for somatic mosaicism and mitotic replicative mutational mechanisms in transmission genetics.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Campbell IM,Yuan B,Robberecht C,Pfundt R,Szafranski P,McEntagart ME,Nagamani SC,Erez A,Bartnik M,Wiśniowiecka-Kowalnik B,Plunkett KS,Pursley AN,Kang SH,Bi W,Lalani SR,Bacino CA,Vast M,Marks K,Patton M,Olofsson P,Pdoi
10.1016/j.ajhg.2014.07.003subject
Has Abstractpub_date
2014-08-07 00:00:00pages
173-82issue
2eissn
0002-9297issn
1537-6605pii
S0002-9297(14)00312-7journal_volume
95pub_type
杂志文章abstract::Monosomy for the X chromosome in humans creates a genetic Achilles' heel for nature to deal with. We report that the human X chromosome appears to have one-third the density of the coding sequence of the autosomes and, because of partial shielding from the high mutation rate of the male sex, that it should also have a...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/303010
更新日期:2000-08-01 00:00:00
abstract::Cerebral cavernous malformations (CCM) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and focal neurological deficits due to cerebral hemorrhages. CCM loci have already been assigned to chromosomes 7q (CCM1), 7p...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/381718
更新日期:2004-02-01 00:00:00
abstract::An astonishing amount of behavioral variation is captured within the more than 350 breeds of dog recognized worldwide. Inherent in observations of dog behavior is the notion that much of what is observed is breed specific and will persist, even in the absence of training or motivation. Thus, herding, pointing, trackin...
journal_title:American journal of human genetics
pub_type: 杂志文章,评审
doi:10.1016/j.ajhg.2007.12.001
更新日期:2008-01-01 00:00:00
abstract::Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2015.12.016
更新日期:2016-02-04 00:00:00
abstract::Epigenetic modifications such as DNA methylation play a key role in gene regulation and disease susceptibility. However, little is known about the genome-wide frequency, localization, and function of methylation variation and how it is regulated by genetic and environmental factors. We utilized the Multiple Tissue Hum...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2013.10.004
更新日期:2013-11-07 00:00:00
abstract::Cells derived from patients with the cancer-prone inherited disorder ataxia-telangiectasia (A-T) show an abnormal response to ionizing radiation-induced DNA damage, such as an increased cell killing and a diminished inhibition of DNA synthesis. The enhanced killing of A-T (group D) cells by X-rays can be corrected by ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1995-02-01 00:00:00
abstract::The heterogeneous nuclear ribonucleoprotein (HNRNP) genes code for a set of RNA-binding proteins that function primarily in the spliceosome C complex. Pathogenic variants in these genes can drive neurodegeneration, through a mechanism involving excessive stress-granule formation, or developmental defects, through mech...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2019.03.024
更新日期:2019-06-06 00:00:00
abstract::To test hypotheses about the origin of modern humans, we analyzed mtDNA sequences, 30 nuclear restriction-site polymorphisms (RSPs), and 30 tetranucleotide short tandem repeat (STR) polymorphisms in 243 Africans, Asians, and Europeans. An evolutionary tree based on mtDNA displays deep African branches, indicating grea...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1002/ajmg.1320570340
更新日期:1995-09-01 00:00:00
abstract::Over the past 20 years, the focus of national efforts to improve K-12 science education has ranged from curriculum and professional development of teachers to the adoption of science standards and high-stakes testing. In spite of this work, students in the United States continue to lag behind their peers in other coun...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2009.05.010
更新日期:2009-07-01 00:00:00
abstract::We report on the identification of a 0.3 Mb inherited recurrent but variable copy-number gain at Xq28 in affected males of four unrelated families with X-linked mental retardation (MR). All aberrations segregate with the disease in the families, and the carrier mothers show nonrandom X chromosome inactivation. Tiling ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2009.10.019
更新日期:2009-12-01 00:00:00
abstract::Some genes that affect development and behavior in mammals are known to be imprinted; and > or = 1% of all mammalian genes are imprinted. Hence, incorporating an imprinting parameter into linkage analysis may increase the power to detect linkage for these traits. Here we propose theoretical justifications for a recent...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/338931
更新日期:2002-03-01 00:00:00
abstract::Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed wi...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2015.01.003
更新日期:2015-03-05 00:00:00
abstract::Timely molecular diagnosis of RB1 mutations enables earlier treatment, lower risk, and better health outcomes for patients with retinoblastoma; empowers families to make informed family-planning decisions; and costs less than conventional surveillance. However, complexity has hindered clinical implementation of molecu...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/345651
更新日期:2003-02-01 00:00:00
abstract::Primary microcephaly is thought to result from genetic defects of the developmental program that generates large brain hemispheres in humans. Autosomal recessive inheritance is likely in most familial cases, and four loci were recently mapped by homozygosity. We report homozygosity mapping of a new locus, MCPH5, with ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/316909
更新日期:2000-12-01 00:00:00
abstract::The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2019.07.005
更新日期:2019-09-05 00:00:00
abstract::We have constructed a primary genetic map spanning most of human chromosome 13. A total of 14 polymorphic DNA sequences and one protein polymorphism provided, after construction of haplotypes, seven markers for the long arm of this chromosome. A panel of cell lines from 30 three-generation families with large sibship ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1986-10-01 00:00:00
abstract::The alkaline phosphatases comprise a multigene enzyme family that hydolyze phosphate esters and are widely distributed in nature. Three main classes have been isolated from humans, the placental, intestinal, and liver/bone/kidney forms. We have mapped the placental and intestinal alkaline phosphatase genes to 2q34-q37...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1987-12-01 00:00:00
abstract::Although recent studies provide evidence for a common genetic basis between complex traits and Mendelian disorders, a thorough quantification of their overlap in a phenotype-specific manner remains elusive. Here, we have quantified the overlap of genes identified through large-scale genome-wide association studies (GW...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2018.08.017
更新日期:2018-10-04 00:00:00
abstract::The putative locus for hereditary mixed polyposis syndrome (HMPS) in a large family of Ashkenazi descent (SM96) was previously reported to map to chromosome sub-bands 6q16-q21. However, new clinical data, together with molecular data from additional family members, have shown 6q linkage to be incorrect. A high-density...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/375144
更新日期:2003-05-01 00:00:00
abstract::Generalized vitiligo is a common autoimmune disorder characterized by the development of white patches of skin and overlying hair due to loss of pigment-forming melanocytes from the involved areas. Family clustering of cases is not uncommon, in a pattern suggestive of multifactorial, polygenic inheritance, and there i...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/375451
更新日期:2003-06-01 00:00:00
abstract::Familial amyotrophic lateral sclerosis (FALS) affects 5%-10% of cases of amyotrophic lateral sclerosis (ALS) and is inherited as an autosomal dominant condition with incomplete penetrance. One-fifth of these cases of FALS are associated with mutations in copper/zinc-dependent superoxide dismutase (SOD1), but the gene ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/377156
更新日期:2003-08-01 00:00:00
abstract::The gene responsible for Krabbe disease, an autosomal recessive disorder caused by deficiency of galactocerebrosidase (GALC), was localized by multipoint linkage analysis on chromosome 14. Eight mapped dinucleotide repeat polymorphisms were tested for linkage to GALC. Two-point linkage analysis demonstrated close link...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1993-12-01 00:00:00
abstract::Studying genomic patterns of human population structure provides important insights into human evolutionary history and the relationship among populations, and it has significant practical implications for disease-gene mapping. Here we describe a principal component (PC)-based approach to studying intracontinental pop...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2009.04.015
更新日期:2009-05-01 00:00:00
abstract::Many individuals with abnormalities of mitochondrial respiratory chain complex III remain genetically undefined. Here, we report mutations (c.288G>T [p.Trp96Cys] and c.643C>T [p.Leu215Phe]) in CYC1, encoding the cytochrome c1 subunit of complex III, in two unrelated children presenting with recurrent episodes of ketoa...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2013.06.015
更新日期:2013-08-08 00:00:00
abstract::We report an unusual molecular defect in the mitochondrially encoded ND1 subunit of NADH ubiquinone oxidoreductase (complex I) in a patient with mitochondrial myopathy and isolated complex I deficiency. The mutation is an inversion of seven nucleotides within the ND1 gene, which maintains the reading frame. The invers...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/302927
更新日期:2000-06-01 00:00:00
abstract::Elsewhere we have reported an efficient method for isolating VNTR (Variable Number of Tandem Repeats) markers. Several of the VNTR markers isolated in those experiments were sequenced, and a DNA sequence of 9 bp (GNNGTGGG) emerged as an apparent consensus sequence for VNTR markers. To confirm this result and to develo...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1988-12-01 00:00:00
abstract::The recent cloning of cDNA encoding the Ca++ release channel (ryanodine receptor) of human sarcoplasmic reticulum has enabled us to use somatic cell hybrids to localize the ryanodine receptor gene (RYR) to the proximal long arm of human chromosome 19. Studies with additional hybrids containing deletions or translocati...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1990-06-01 00:00:00
abstract::Renal agenesis and hypodysplasia (RHD) are major causes of pediatric chronic kidney disease and are highly genetically heterogeneous. We conducted whole-exome sequencing in 202 case subjects with RHD and identified diagnostic mutations in genes known to be associated with RHD in 7/202 case subjects. In an additional a...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2017.09.018
更新日期:2017-11-02 00:00:00
abstract::Nemaline myopathy (NM) is a clinically and genetically heterogeneous disorder characterized by muscle weakness and the presence of nemaline bodies (rods) in skeletal muscle. Disease-causing mutations have been reported in five genes, each encoding a protein component of the sarcomeric thin filament. Recently, we ident...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/320605
更新日期:2001-06-01 00:00:00
abstract::Genome-wide association studies are routinely conducted to identify genetic variants that influence complex disorders. It is well known that failure to properly account for population or pedigree structure can lead to spurious association as well as reduced power. We propose a method, ROADTRIPS, for case-control assoc...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2010.01.001
更新日期:2010-02-12 00:00:00