Benjamin D. Solomon

Parent-of-origin-specific signatures of de novo mutations

De novo mutations (DNMs) originating in gametogenesis are an important source of genetic variation. We use a data set of 7,216 autosomal DNMs with resolved parent of origin from whole-genome sequencing of 816 parent–offspring trios to investigate differences between maternally and paternally derived DNMs and study the underlying mutational mechanisms. Our results show that the number of DNMs in offspring increases not only with paternal age, but also with maternal age, and that some genome regions show enrichment for maternally derived DNMs. We identify parent-of-origin-specific mutation signatures that become more pronounced with increased parental age, pointing to different mutational mechanisms in spermatogenesis and oogenesis. Moreover, we find DNMs that are spatially clustered to have a unique mutational signature with no significant differences between parental alleles, suggesting a different mutational mechanism. Our findings provide insights into the molecular mechanisms that underlie mutagenesis and are relevant to disease and evolution in humans.

Expanding the phenotypic spectrum in EP300-related Rubinstein-Taybi syndrome.

Rubinstein–Taybi syndrome (RSTS) can be caused by heterozygous mutations or deletions involving CREBBP or, less commonly, EP300. To date, only 15 patients with EP300 mutations have been clinically described. Frequently reported manifestations in these patients include characteristic facial and limb features, varying degrees of neurocognitive dysfunction, and maternal preeclampsia. Other congenital anomalies are less frequently reported. We describe a child found to have a de novo EP300 mutation (c.4933C>T, predicted to result in p.Arg1645X) through research‐based whole‐genome sequencing of the family trio. The childs presentation involved dysmorphic features as well as unilateral renal agenesis, a myelomeningocele, and minor genitourinary anomalies. The involvement of congenital anomalies in all 16 clinically described patients with EP300 mutations (25% of which have been identified by “hypothesis free” methods, including microarray, exome, and whole‐genome sequencing) is reviewed. In summary, genitourinary anomalies have been identified in 38%, cardiovascular anomalies in 25%, spinal/vertebral anomalies in 19%, other skeletal anomalies in 19%, brain anomalies in 13%, and renal anomalies in 6%. Our patient expands the phenotypic spectrum in EP300‐related RSTS; this case demonstrates the evolving practice of clinical genomics related to increasing availability of genomic sequencing methods.

Obstacles and opportunities for the future of genomic medicine

The pace of the advancement of genomic sequencing over the last decade – especially within the last 5 years – has been astounding. What initially required billions of dollars and hundreds of thousands of person-hours spread out over dozens of institutes in multiple countries can now be accomplished more accurately by one person over the course of a week, for the cost of about a thousand dollars (Lander et al. 2001; Hayden 2014). And concerns about the “thousand dollar genome” requiring an analysis costing hundreds of times that are being supplanted by the ability to leverage existing clinical/research infrastructures and through improved pipelines (Dewey et al. 2014). These pipelines include commercial offerings that allow rapid and highly sophisticated analyses based on proprietary literature curation and private variant databases (Mardis 2010).

A Child's HLA-DRB1 genotype increases maternal risk of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) disproportionately affects women of reproductive age. During pregnancy, women are exposed to various sources of fetal material possibly constituting a significant immunologic exposure relevant to the development of SLE. The objective of this study was to investigate whether having any children who carry DRB1 alleles associated with SLE increase the risk of maternal SLE. This case-control study is based on the University of California, San Francisco Mother-Child Immunogenetic Study and from studies at the Inova Translational Medicine Institute. Analyses were conducted using data for 1304 mothers (219 cases/1085 controls) and their respective 1664 children. We selected alleles based on their known association with risk of SLE (DRB1*03:01, *15:01, or *08:01) or Epstein-Barr virus (EBV) glycoproteins (*04:01) due to the established EBV association with SLE risk. We used logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for each allele of interest, taking into account maternal genotype and number of live births. We found an increase in risk of maternal SLE associated with exposure to children who inherited DRB1*04:01 from their father (OR 1.9; 95% CI, 1.1-3.2), among *04:01 allele-negative mothers. Increased risk was only present among mothers who were positive for one or more SLE risk-associated alleles (*03:01, *15:01 and/or *08:01). We did not find increased risk of maternal SLE associated with any other tested allele. These findings support the hypothesis that a childs alleles inherited from the father influence a mothers subsequent risk of SLE.

Aberrant splicing induced by the most common EPG5 mutation in an individual with Vici syndrome

Sir, Recently, a study describing the clinical and genetic data of 50 patients (30 families) with Vici syndrome (OMIM 242840) was published in Brain (Byrne et al. , 2016 b ). Vici syndrome is a severe autosomal recessive condition recently found to be caused by mutations in the EPG5 gene (NG_042838.1) (Cullup et al. , 2013). Principal features of Vici syndrome include neurological sequelae (agenesis of the corpus callosum, profound developmental delay, and progressive microcephaly), neonatal cataracts, hypopigmentation involving both skin and hair, progressive dilated or hypertrophic cardiomyopathy, and both B and T cell-related immunodeficiency (Byrne et al. , 2016 a , b ). The most common mutation identified in Vici syndrome patients is EPG5 NM_020964.2; c.1007A>G p.Gln336Arg. Based on the two large cohorts of patients recently studied (Cullup et al. , 2013; Byrne et al. , 2016 b ), this mutation accounts for >10% (9/86) of mutations. Ancestry data from previous studies show that this mutation may be associated with Ashkenazi descent (Byrne et al. , 2016 a , b ). This variant was not detected in whole genome sequencing data from our cohort of 4456 unrelated adults seen at the Inova Translational Medicine Institute (Bodian et al. , 2014, 2016). This variant is seen with a frequency of 3.129 ×10−5 in the European (non-Finnish) population of Exome Aggregation Consortium (ExAC) and has thus far never been reported in other ExAC populations (ExAC, 2016; http://exac.broadinstitute.org). The EGP5 c.1007A>G mutation has been suggested to affect splicing through in silico prediction models, though multiple predictions are contradictory [Human Splicing Finder (Desmet et al. , 2009; http://www.umd.be/HSF3/HSF.html: −6%) and NNSPLICE (Reese et al. , 1997; http://www.fruitfly.org/seq_tools/splice.html: −100%)]. Likewise, in silico predictions of the missense mutation are in disagreement with regards to its pathogenicity [PolyPhen-2 (Adzhubei et al. , …

Increased risk of rheumatoid arthritis among mothers with children who carry DRB1 risk-associated alleles

Objective To investigate whether a child’s genotype affects a mother’s risk of rheumatoid arthritis (RA) beyond the risk associated with her genotype and to test whether exposure to fetal alleles inherited from the father increases risk of RA among mothers without risk alleles. Methods A case–control study was conducted among 1165 mothers (170 cases/995 controls) and their respective 1482 children. We tested the association between having any child with alleles encoding amino acids (AAs) associated with RA including the ‘shared epitope’ (SE) and DERAA AA sequences at positions 70–74; AA valine, lysine and alanine at positions 11, 71 and 74 of HLA-DRB1; aspartic acid at position 9 of HLA-B and phenylalanine at position 9 of DPB1. We used logistic regression models to estimate OR and 95% CI for each group of alleles, adjusting for maternal genotype and number of live births. Results We found increased risk of RA among mothers who had any child with SE (OR 3.0; 95% CI 2.0 to 4.6); DERAA (OR 1.7; 95% CI 1.1 to 2.6); or valine (OR 2.3; 95% CI 1.6 to 3.5), lysine (OR 2.3; 95% CI 1.5 to 3.4) and alanine (OR 2.8; 95% CI 1.2 to 6.4) at DRB1 positions 11, 71 and 74, respectively. Among non-carrier mothers, increased risk of RA was associated with having children who carried DERAA (OR 1.7; 95% CI 1.0 to 2.7) and alleles encoding lysine at DRB1 position 71 (OR 2.3; 95% CI 1.5 to 4.8). Conclusion Findings support the hypothesis that a child’s genotype can contribute independently to risk of RA among mothers.

Putting the Pieces Together: Clinically Relevant Genetic and Genomic Resources for Hospitalists and Neonatologists.

Genetic conditions are individually rare but are common in aggregate, and they often present in the neonatal and early pediatric periods. These conditions are often severe, can be difficult to diagnose and manage, and may heavily affect patients, families, health care systems, and society. Because of recent technological advances, the availability and uptake of genetic and genomic testing are increasing rapidly. However, there is a dearth of trained geneticists and genetic counselors to help guide and explain these conditions and relevant tests. To help hospitalists, neonatologists, and related practitioners navigate this complex and evolving field, we have compiled a list of free (mostly Web-based) resources relevant to the diagnosis and management of genetic conditions and related disorders. These resources, which we describe individually, can be useful for nongeneticist clinicians, and some also include material that can be used to explain concepts and conditions to patients or families. The resources presented are divided into the following categories (which overlap): general information, databases of genetic conditions, resources that can help generate differential diagnoses, databases of genetic testing laboratories (to help with logistics of ordering tests), information on newborn screening, and other resources. We also include a separate list of helpful textbooks and manuals. We conclude with 2 examples describing how some of these resources would be used by a pediatric hospitalist or neonatologist during the inpatient management of a child with a suspected genetic condition.

GLI2 mutations typically result in pituitary anomalies with or without postaxial polydactyly

GLI2 Mutations Typically Result in Pituitary Anomalies With or Without Postaxial Polydactyly Kelly A. Bear and Benjamin D. Solomon* Department of Pediatrics, Tripler Army Medical Center, Honolulu, Hawaii Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia Inova Translational Medicine Institute and Inova Children’s Hospital, Inova Health System, Falls Church, Virginia Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, Virginia

Germline de novo mutation clusters arise during oocyte aging in genomic regions with high double-strand-break incidence

Clustering of mutations has been observed in cancer genomes as well as for germline de novo mutations (DNMs). We identified 1,796 clustered DNMs (cDNMs) within whole-genome-sequencing data from 1,291 parent–offspring trios to investigate their patterns and infer a mutational mechanism. We found that the number of clusters on the maternal allele was positively correlated with maternal age and that these clusters consisted of more individual mutations with larger intermutational distances than those of paternal clusters. More than 50% of maternal clusters were located on chromosomes 8, 9 and 16, in previously identified regions with accelerated maternal mutation rates. Maternal clusters in these regions showed a distinct mutation signature characterized by C>G transversions. Finally, we found that maternal clusters were associated with processes involving double-strand-breaks (DSBs), such as meiotic gene conversions and de novo deletion events. This result suggested accumulation of DSB-induced mutations throughout oocyte aging as the mechanism underlying the formation of maternal mutation clusters.Analysis of whole-genome sequencing data from 1,291 parent–offspring trios identifies patterns of clustered de novo mutations. Clusters increase in number with maternal age and are associated with DNA double-strand-break processes.

Common genetic causes of holoprosencephaly are limited to a small set of evolutionarily conserved driver genes of midline development coordinated by TGF-β, hedgehog, and FGF signaling

Here, we applied targeted capture to examine 153 genes representative of all the major vertebrate developmental pathways among 333 probands to rank their relative significance as causes for holoprosencephaly (HPE). We now show that comparisons of variant transmission versus nontransmission among 136 HPE Trios indicates some reported genes now lack confirmation, while novel genes are implicated. Furthermore, we demonstrate that variation of modest intrinsic effect can synergize with these driver mutations as gene modifiers.