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Bladder exstrophy (BE) is a rare, lower ventral midline defect with the bladder and part of the urethra exposed. The etiology of BE is unknown but thought to be influenced by genetic variation with more recent studies suggesting a role for rare variants. As such, we conducted paired-end exome sequencing in 26 child/mother/father trios. Three children had rare (allele frequency ≤ 0.0001 in several public databases) inherited variants in TSPAN4, one with a loss-of-function variant and two with missense variants. Two children had loss-of-function variants in TUBE1. Four children had rare missense or nonsense variants (one per child) in WNT3, CRKL, MYH9, or LZTR1, genes previously associated with BE. We detected 17 de novo missense variants in 13 children and three de novo loss-of-function variants (AKR1C2, PRRX1, PPM1D) in three children (one per child). We also detected rare compound heterozygous loss-of-function variants in PLCH2 and CLEC4M and rare inherited missense or loss-of-function variants in additional genes applying autosomal recessive (three genes) and X-linked recessive inheritance models (13 genes). Variants in two genes identified may implicate disruption in cell migration (TUBE1) and adhesion (TSPAN4) processes, mechanisms proposed for BE, and provide additional evidence for rare variants in the development of this defect.

Van den Ende-Gupta syndrome (VDEGS) is a rare autosomal recessive condition characterized by distinctive facial and skeletal features, and in most affected persons, by biallelic pathogenic variants in SCARF2. We review the type and frequency of the clinical features in 36 reported individuals with features of VDEGS, 15 (42%) of whom had known pathogenic variants in SCARF2, 6 (16%) with negative SCARF2 testing, and 15 (42%) not tested. We also report three new individuals with pathogenic variants in SCARF2 and clinical features of VDEGS. Of the six persons without known pathogenic variants in SCARF2, three remain unsolved despite extensive genetic testing. Three were found to have pathogenic ABL1 variants using whole exome sequencing (WES) or whole genome sequencing (WGS). Their phenotype was consistent with the congenital heart disease and skeletal malformations syndrome (CHDSKM), which has been associated with ABL1 variants. Of the three unsolved cases, two were brothers who underwent WGS and targeted long-range sequencing of both SCARF2 and ABL1, and the third person who underwent WES and RNA sequencing for SCARF2. Because these affected individuals with classical features of VDEGS lacked a detectable pathogenic SCARF2 variant, genetic heterogeneity is likely. Our study shows the importance of performing genetic testing on individuals with the VDEGS "phenotype," either as a targeted gene analysis (SCARF2, ABL1) or WES/WGS. Additionally, individuals with the combination of arachnodactyly and blepharophimosis should undergo echocardiography while awaiting results of molecular testing due to the overlapping physical features of VDEGS and CHDSKM.

Transport of activated nucleotide-sugars into the Golgi is critical for proper glycosylation and mutations in these transporters cause a group of rare genetic disorders termed congenital disorders of glycosylation. We performed exome sequencing on an individual with a profound neurological presentation and identified rare compound heterozygous mutations, p.Thr156Arg and p.Glu196Lys, in the CMP-sialic acid transporter, SLC35A1. Patient primary fibroblasts and serum showed a considerable decrease in the amount of N- and O-glycans terminating in sialic acid. Direct measurement of CMP-sialic acid transport into the Golgi showed a substantial decrease in overall rate of transport. Here we report the identification of the third patient with CMP-sialic acid transporter deficiency, who presented with severe neurological phenotype, but without hematological abnormalities.

Defects in genes encoding the isoforms of the laminin alpha subunit have been linked to various phenotypic manifestations, including brain malformations, muscular dystrophy, ocular defects, cardiomyopathy, and skin abnormalities. We report here a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin alpha-5 subunit gene (LAMA5). The variant c.8046C>T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had muscle weakness, myopia, and facial tics. Magnetic resonance imaging of brain showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation revealed 50% decrement of compound muscle action potential amplitudes and 250% facilitation immediately after exercise, Endplate studies identified a profound reduction of the endplate potential quantal content and endplates with normal postsynaptic folding that were denuded or partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin alpha-5 to SV2A and impaired laminin-521 cell-adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with a LAMA5 mutation expands the list of phenotypes associated with defects in genes encoding alpha-laminins.

Toriello and Carey described a provisionally-unique syndrome comprised of agenesis of the corpus callosum, Pierre Robin anomaly, and a characteristic facial phenotype. Because the condition affected siblings, this entity was postulated to be an autosomal recessive multiple anomaly syndrome. Several patients were subsequently reported, and over time, it became apparent that the Toriello-Carey syndrome was etiologically heterogeneous. Based on previous reports, it is estimated that at least 20% of patients with a clinical diagnosis of Toriello-Carey syndrome have a chromosomal anomaly as the basis of the phenotype. However, no basis for the non-chromosomal cases has been found. This review summarizes the literature to date and provides speculation regarding the possible explanations for failing to find the cause of Toriello-Carey syndrome. © 2016 Wiley Periodicals, Inc.

Increasing numbers of congenital disorders of glycosylation (CDG) have been reported recently resulting in an expansion of the phenotypes associated with this group of disorders. SRD5A3 codes for polyprenol reductase which converts polyprenol to dolichol. This is a major pathway for dolichol biosynthesis for N-glycosylation, O-mannosylation, C-mannosylation, and GPI anchor synthesis. We present the features of five individuals (three children and two adults) with mutations in SRD5A3 focusing on the variable eye and skin involvement. We compare that to 13 affected individuals from the literature including five adults allowing us to delineate the features that may develop over time with this disorder including kyphosis, retinitis pigmentosa, and cataracts. © 2016 Wiley Periodicals, Inc.

Clinical and research uses of exome and whole genome sequencing (ES/WGS) are growing rapidly. An enhanced understanding of how individuals conceptualize and communicate about sequencing results is needed to ensure effective, mutual exchange of information between care providers and patients and between researchers and participants. Focus groups and interviews participants were recruited to discuss their attitudes and preferences for receiving hypothetical results from ES/WGS. African Americans were intentionally oversampled. We qualitatively analyzed participants' speech to identify unsolicited metaphorical language pertaining to genes and health, and grouped these occurrences into metaphorical concepts. Participants compared genetic information to physical objects including tools, weapons, contents of boxes, and formal documents or reports. These metaphorical concepts centered on several key themes, including locus of control; containment versus release of information; and desirability, usability, interpretability, and ownership of genetic results. Metaphorical language is often used intentionally or unintentionally in discussions about receiving results from ES/WGS in both clinical and research settings. Awareness of the use of metaphorical language and attention to its varied meanings facilitates effective communication about return of ES/WGS results. In turn, both should foster shared and informed decision-making and improve the translation of genetic information by clinicians and researchers.

Speech and language deficits are commonly associated with Kabuki syndrome. Yet little is known regarding the specific symptomatology of these disorders, preventing use of targeted treatment programs. Here we detail speech and language in 16 individuals with Kabuki syndrome (thirteen with KMT2D mutations, one with a KDM6A mutation, and two mutation-negative cases), aged 4-21 years. The most striking speech deficit was dysarthria, characterised by imprecise consonants, harsh vocal quality, hypernasality, reduced rate and stress, and distorted pitch. Oromotor functioning was also impaired. Delayed, rather than disordered, articulation and phonology was common. Both receptive and expressive language abilities were reduced in the majority and deficits were noted across all language sub-domains (i.e., semantics, syntax, morphology, and pragmatics) with no clear differentiation or specific language profile. Individuals with Kabuki syndrome present with a heterogenous pattern of oromotor, speech, and language deficits. This variability fits with the multisystem nature of the disorder, which may encompass neurological, orofacial structural, hearing, and cognitive deficits, any or all of which may contribute to speech or language impairment. Our results suggest that all individuals with Kabuki syndrome have some level of communication deficit, warranting speech pathology involvement in all cases.

Distal arthrogryposis (DA) syndromes are a group of disorders characterized by multiple congenital contractures. DA type 2A (DA2A or Freeman-Sheldon syndrome), caused by mutations in MYH3, is typically considered the most severe of the DA syndromes. However, there is wide phenotypic variability among individuals with DA2A. We characterized genotype-phenotype relationships in 46 families with DA2A. MYH3 mutations were found in 43/46 (93%) kindreds, with three mutations (p.T178I, p.R672C, and p.R672H) explaining 39/43 (91%) of cases. Phenotypic severity varied significantly by genotype (P=0.0055). Individuals with p.T178I were the most severely affected with both facial contractures and congenital scoliosis. Classification of individuals with DA2A into phenotypic groups of varying severity should facilitate providing families with more accurate information about natural history and suggests that individuals might benefit from personalized medical management motivated by MYH3 genotype.

Opsismodysplasia (OMIM258480) is a rare, autosomal recessive skeletal dysplasia with delayed bone maturation. It was first described in 1977 by Zonana et al. and named opsismodysplasia by Maroteaux et al. in 1984 [Maroteaux et al., 1982; Maroteaux et al., 1984]. The clinical features include micromelia with extremely short hands and feet, as well as facial dysmorphism including prominent eyebrows, large open fontanels, depressed nasal bridge, short anteverted nose and relatively long philtrum. Some patients were also reported as having severe renal phosphate wasting [Below et al., 2013]. The characteristic radiographic features include severe platyspondyly, shortened long bones with dramatically delayed epiphyseal ossification, and characteristic hands with markedly delayed carpal ossification, short squared metacarpals and phalanges, and metaphyseal cupping [Beemer and Kozlowski 1994; Cormier-Daire et al., 2003; Maroteaux et al., 1984; Santos and Saraiva 1995; Tyler et al., 1999; Zonana et al., 1977]. The mortality is highly variable, ranging from death secondary to respiratory failure during the first few years of life to survival into adulthood.

Exome sequencing and whole genome sequencing (ES/WGS) present patients and research participants with the opportunity to benefit from a broad scope of genetic results of clinical and personal utility. Yet, this potential for benefit also risks disenfranchising populations such as African Americans (AAs) that are already underrepresented in genetic research and utilize genetic tests at lower rates than other populations. Understanding a diverse range of perspectives on consenting for ES/WGS and receiving ES/WGS results is necessary to ensure parity in genomic health care and research. We conducted a series of 13 focus groups (n = 76) to investigate if and how attitudes toward participation in ES/WGS research and return of results from ES/WGS differ between self-described AAs and non-AAs. The majority of both AAs and non-AAs were willing to participate in WGS studies and receive individual genetic results, but the fraction not interested in either was higher in AAs. This is due in part to different expectations of health benefits from ES/WGS and how results should be managed. Our results underscore the need to develop and test culturally tailored strategies for returning ES/WGS results to AAs.

Exome and whole genome sequencing (ES/WGS) offer potential advantages over traditional approaches to diagnostic genetic testing. Consequently, use of ES/WGS in clinical settings is rapidly becoming commonplace. Yet there are myriad moral, ethical, and perhaps legal implications attached to the use of ES and health care professionals and institutions will need to consider these implications in the context of the varied practices and policies of ES service providers. We developed "core elements" of content and procedures for informed consent, data sharing, and results management and a quantitative scale to assess the extent to which research protocols met the standards established by these core elements. We then used these tools to evaluate the practices and policies of each of the 6 U.S. CLIA-certified labs offering clinical ES. Approaches toward informed consent, data sharing, and results return vary widely among ES providers as do the overall potential merits and disadvantages of each, and more importantly, the balance between the two.

The distal arthrogryposis (DA) syndromes are a group of disorders characterized by non-progressive congenital contractures of the limbs. Mutations that cause distal arthrogryposis syndromes have been reported in six genes, each of which encodes a component of the contractile apparatus of skeletal myofibers. However, these reports have usually emanated from gene discovery efforts and thus potentially bias estimates of the frequency of pathogenic mutations at each locus. We characterized the spectrum of pathogenic variants in a cohort of 153 cases of DA1 (n = 48) and DA2B (n = 105). Disease-causing mutations in 56/153 (37%) kindreds including 14/48 (29%) with DA1 and 42/105 (40%) with DA2B were distributed nearly equally across TNNI2, TNNT3, TPM2, and MYH3. In TNNI2, TNNT3, and TPM2 the same mutation caused DA1 in some families and DA2B in others. We found no significant differences among the clinical characteristics of DA by locus or between each locus and DA1 or DA2B. Collectively, the substantial overlap between phenotypic characteristics and spectrum of mutations suggests that DA1 and DA2B should be considered phenotypic extremes of the same disorder.

Isolated clubfoot is a relatively common birth defect that affects approximately 4,000 newborns in the US each year. Calf muscles in the affected leg(s) are underdeveloped and remain small even after corrective treatment. This observation suggests that variants in genes that influence muscle development are priority candidate risk factors for clubfoot. This contention is further supported by the discovery that mutations in genes that encode components of the muscle contractile complex (MYH3, TPM2, TNNT3, TNNI2, and MYH8) cause congenital contractures, including clubfoot, in distal arthrogryposis (DA) syndromes. Interrogation of fifteen genes encoding proteins that control myofiber contractility in a cohort of both nonHispanic white (NHW) and Hispanic families, identified positive associations (p

Kabuki syndrome is a rare, multiple malformation disorder characterized by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability. Simplex cases make up the vast majority of the reported cases with Kabuki syndrome, but parent-to-child transmission in more than a half-dozen instances indicates that it is an autosomal dominant disorder. We recently reported that Kabuki syndrome is caused by mutations in MLL2, a gene that encodes a Trithorax-group histone methyltransferase, a protein important in the epigenetic control of active chromatin states. Here, we report on the screening of 110 families with Kabuki syndrome. MLL2 mutations were found in 81/110 (74%) of families. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, while a transmitted MLL2 mutation was found in two of three familial cases. The majority of variants found to cause Kabuki syndrome were novel nonsense or frameshift mutations that are predicted to result in haploinsufficiency. The clinical characteristics of MLL2 mutation-positive cases did not differ significantly from MLL2 mutation-negative cases with the exception that renal anomalies were more common in MLL2 mutation-positive cases. These results are important for understanding the phenotypic consequences of MLL2 mutations for individuals and their families as well as for providing a basis for the identification of additional genes for Kabuki syndrome.

We report on a three-generation family with distal arthrogryposis type 5 (DA5). The family has four affected members in three generations with an apparent autosomal dominant pattern of inheritance. Three affected individuals were examined. All have distal joint contractures with absent flexion creases, limited mobility of all small and large joints, unusual stance with shortened heel cords and pes cavus, firm muscles, short stature, decreased extraocular movements, and pectus excavatum. The propositus has pulmonary hypertension secondary to chronic hypoxia from restrictive chest disease, alveolar hypoventilation, and residence at 7,000 feet above sea level. Cardiac catheterization documented pulmonary artery pressure of 54 mmHg and a pulmonary capillary wedge pressure of 10 mmHg. Pulmonary function tests showed severe chest restriction (forced vital capacity 30% of predicted; total lung capacity 51% predicted); and reduction of maximal inspiratory and expiratory pressures. Arterial blood gases documented alveolar hypoventilation. Restrictive chest disease is a component of DA5. This implies involvement of the skeletal, and/or respiratory muscles. All individuals diagnosed with DA5 should be evaluated for chest disease, alveolar hypoventilation, as treatment of chronic hypoxia may delay or reverse pulmonary hypertension.

In science and medicine there are occasional major advances that facilitate transformations of a field. The application of next-generation massively parallel sequencing technologies coupled with powerful computational approaches to discover genes for Mendelian disorders is arguably such a major advance [Biesecker, 2010]. Just three years ago, the strategy of exome sequencing (ES) followed by discrete filtering was introduced and shown to be a potential approach to identify the genes underlying Mendelian conditions [Choi et al., 2009; Ng et al., 2010; Ng et al., 2009]. Since then, ES and whole genome sequencing (WGS) [Lupski et al., 2010] have been used to explain the cause of dozens of disorders [Bamshad et al., 2011; Claudia Gonzaga-Jauregui, 2012; Gilissen et al., 2011] including those transmitted as X-linked, autosomal recessive [Bilguvar and et al., 2010], and autosomal dominant traits [Choi et al. 2011]; as well as phenotypes caused by de novo dominant mutations [Choate et al. 2010; O'Roak et al. 2011; Vissers et al. 2010] and somatic mosaicism [Lindhurst et al. 2011]. Given the technical and analytical improvements expected over the next several years, the application of ES/WGS-based strategies will enable the identification of the genes underlying a very large fraction of all known Mendelian disorders for which the genetic basis is not yet known — at a small fraction of the current cost for discovery per disorder. Based on these advances, exploring all Mendelian disorders should become an imperative for the worldwide human genetics community. The discoveries made through such exploration would be of enormous service to families, and will provide novel entry points to investigate the mechanisms underlying disease development. Such an effort would, however, be very ambitious, requiring an unprecedented degree of cooperation and coordination in the field of medical genetics and the assistance of patients and families from around the world. A global initiative to explore all Mendelian conditions is now emerging. The initiative, which includes the International Rare Diseases Research Consortium, the Finding of Rare Disease Genes (FORGE) in Canada, and centers in Europe, East Asia and elsewhere, will establish the necessary collaborative framework and physical infrastructure to achieve this goal. In the United States, the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) have partnered to support this effort at three Centers for Mendelian Genomics (CMGs): the Center for Mendelian Genomics at the University of Washington; the Center for Mendelian Disorders at Yale University; and the Baylor-Johns Hopkins Center for Mendelian Genomics at Baylor College of Medicine and the Johns Hopkins University. The CMGs have four major goals: (1) to ascertain samples for all Mendelian disorders for which the genetic basis is not yet understood from clinicians and investigators around the world by developing a ‘public list’ of samples and by coordinating submissions to the NIH program with those of other international programs; (2) to improve the efficiency of the sequencing pipeline and quality of exome and genome data through ongoing technology innovation; (3) to determine the genetic basis for as many Mendelian conditions as possible; and (4) to disseminate methods and data to facilitate gene discovery by investigators working independently across the globe. The CMGs will study disorders with age of onset across the entire lifespan including well-delineated, known Mendelian phenotypes as well as novel phenotypes thought to be Mendelian on the basis of their segregation patterns in families. Initially, the “public list” will be a catalog of collected DNA samples, organized by condition, that have entered the sequencing pipeline at any one of the CMGs. Next, this list will expand to include all of the Mendelian disorders for which the CMGs have solicited DNA samples, sequencing status, and the results obtained to date. Since the availability of a sufficient number of samples from clinically well-characterized cases and families will be critical to the discovery of genes for all Mendelian disorders, one aim of the public list is to facilitate coordination of sample collection and implementation of ES among clinicians and researchers around the world. Ultimately, the CMGs aim to develop the list into a comprehensive community resource that provides information on samples that are available worldwide for concerted disease gene discovery efforts. With this introduction, we would like to engage the medical genetics community to join with us and collaborate with the CMGs by submitting information about familial conditions, adding samples to the effort from individuals or families with rare Mendelian disorders to stimulate collaborations and eventually new insights. Since many of these conditions are rare, and often with locus heterogeneity, multiple investigators will need to contribute samples from individuals and families with the same diagnosis to improve chances for finding and validating candidate genes and variants. Following sequencing and analysis, the CMGs will return the results to the submitters, and will collaborate with investigators to facilitate further analysis, functional studies, and, ultimately publication. Results will be provided to the collaborating investigators as soon as possible. Collaborating investigators will have data exclusivity for a minimum of six months to ensure ample time to conduct follow up studies and prepare manuscripts for publication. The development of a public list will ensure transparency and facilitate communications about progress within and beyond the medical genetics community; this list will soon be accessible via the CMG website (http://mendelian.org). While the workflow will vary among CMGs, several key common practices across the CMGs will enable high-quality data production and analysis with partnering contributors. Phenotypic information associated with each sample and family will be collected and evaluated to increase diagnostic precision, identify phenotypic features that clarify genetic heterogeneity and aid in the identification of previously unrecognized disorders. DNA samples will be genotyped using low-cost, genome-wide marker arrays to provide a unique profile for sample tracking, to identify copy number variation (CNVs) and to provide genetic information for subsequent analysis of sequence variations (large and small insertion-deletions) underlying these conditions. These approaches, when applied to well-characterized pedigrees, will aid in finding the genomic intervals shared among all (or nearly all) cases, and reduce the genomic search space and speed the subsequent identification of candidate gene(s) by the collaborating investigators [Sobreira et al., 2010]. The success of this effort will require collaboration at an unprecedented scale in the field of human genetics. The CMGs and their global partners welcome partnering scientists and clinicians with samples or families affected with a Mendelian condition to collaborate with us by submitting inquiries to gro.nailednem@lednemg. The CMGs have partnered with Wiley-Liss and the American Journal of Medical Genetics (AJMG) to advertise in each issue to its worldwide readership of clinical and medical geneticists. The corresponding author of each manuscript accepted by the Journal will be provided with information about the CMGs. This is a welcome and important partnership since the AJMG is a well-known forum for the delineation of new syndromes and for reporting the description of novel rare, Mendelian conditions. Similarly, the Online Mendelian Inheritance in Man (OMIM; www.OMIM.org) catalog will provide a means for quickly disseminating summaries of newly discovered genes for known Mendelian disorders and adding newly delineated disorders to the OMIM catalog. We welcome the possibilities for other scientists, international journals and websites to link to the CMG site (http://mendelian.org). We ask clinicians and scientists to collaborate with us by submitting cases and families. The key drivers for the CMGs are to serve the scientific community and the individuals and families with rare diseases by improving knowledge about these rare conditions. By making specific diagnoses and exploring on a genome level the relationships between sequence variation and phenotype, collaboratively we can achieve more comprehensive pre-symptomatic or carrier screening. Additionally, the knowledge obtained from these efforts could initiate the exploration of new and/or improved therapeutics for these conditions. The CMG mechanism will eliminate significant financial and technical barriers for clinicians who wish to gain deeper understanding of genetic disorders and will catalyze interactions across the worldwide biomedical community to utilize these genotype/phenotype correlations to drive a deeper understanding of the biology of disease. The application of powerful new genomic approaches in genetics will provide an unprecedented view into the molecular basis of many, if not most, unexplained Mendelian phenotypes. The CMG will provide the community with access to production infrastructure, bioinformatics support, and analytical expertise. The challenge to the human genetics community is to help initiate this new phase of medical genomics and take advantage of this new opportunity by providing the resources for such studies that obviously cannot occur without finding and characterizing the patients and their families. Please contact us at gro.nailednem@lednemg or through the web portals of the individual centers with questions or with samples to submit.