Autosomal recessive hypotrichosis with loose anagen hairs associated with TKFC mutations.

BACKGROUND: Loose anagen hair is a rare form of impaired hair anchorage in which anagen hairs that lack inner and outer root sheaths can be gently and painlessly plucked from the scalp. This condition usually occurs in children and is often self-limiting. A genetic basis for the disorder has been suggested but not proven. A better understanding the aetiology of loose anagen hair may improve prevention and treatment strategies. OBJECTIVES: To identify a possible genetic basis of loose anagen hair using next-generation DNA sequencing and functional analysis of variants identified. METHODS: In this case study, whole-exome sequencing analysis of a pedigree with one affected individual with features of loose anagen hair was performed. RESULTS: The patient was found to be compound heterozygous for two single-nucleotide substitutions in TKFC resulting in the following missense mutations: c.574G> C (p.Gly192Arg) and c.682C> T (p.Arg228Trp). Structural analysis of human TKFC showed that both mutations are located near the active site cavity. Kinetic assays of recombinant proteins bearing either of these amino acid substitutions showed almost no dihydroxyacetone kinase or D-glyceraldehyde kinase activity, and FMN cyclase activity reduced to just 10% of wildtype catalytic activity. CONCLUSIONS: TKFC missense mutations may predispose to the development of loose anagen hairs. Identification of this new biochemical pathobiology expands the metabolic and genetic basis of hypotrichosis.

Genotype-phenotype correlation in a large English cohort of patients with autosomal recessive ichthyosis.

BACKGROUND: Recessive forms of congenital ichthyosis encompass a group of rare inherited disorders of keratinization leading to dry, scaly skin. So far, 13 genes have been implicated, but there is a paucity of data on genotype-phenotype correlation in some populations. OBJECTIVES: We compiled an English cohort of 146 individuals with recessive ichthyosis and assessed genotype-phenotype correlation. METHODS: Deep phenotyping was undertaken by history-taking and clinical examination. DNA was screened for mutations using a next-generation sequencing ichthyosis gene panel and Sanger sequencing. RESULTS: Cases were recruited from 13 National Health Service sites in England, with 65% of patients aged < 16 years at enrolment. Pathogenic biallelic mutations were found in 83% of cases, with the candidate gene spread as follows: TGM1 29%, NIPAL4 12%, ABCA12 12%, ALOX12B 9%, ALOXE3 7%, SLC27A4 5%, CERS3 3%, CYP4F22 3%, PNPLA1 2%, SDR9C7 1%. Clinically, a new sign, an anteriorly overfolded ear at birth, was noted in 43% of patients with ALOX12B mutations. The need for intensive care stay (P = 0·004), and hand deformities (P < 0·001), were associated with ABCA12 mutations. Self-improving collodion ichthyosis occurred in 8% of the cases (mostly TGM1 and ALOX12B mutations) but could not be predicted precisely from neonatal phenotype or genotype. CONCLUSIONS: These data refine genotype-phenotype correlation for recessive forms of ichthyosis in England, demonstrating the spectrum of disease features and comorbidities, as well as the gene pathologies therein. Collectively, the data from these patients provide a valuable resource for further clinical assessment, improving clinical care and the possibility of future stratified management. What's already known about this topic? Recessive forms of ichthyosis are rare but often difficult to diagnose. Mutations in 13 genes are known to cause recessive forms of ichthyosis: ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, ST14 and TGM1. Some phenotypic features may associate with certain gene mutations, but paradigms for genotype-phenotype correlation need refining. What does this study add? The genotypic spectrum of recessive ichthyosis in England (based on 146 cases) comprises TGM1 (29%), NIPAL4 (12%), ABCA12 (12%), ALOX12B (9%), ALOXE3 (7%), SLC27A4 (5%), CERS3 (3%), CYP4F22 (3%), PNPLA1 (2%) and SDR9C7 (1%). New or particular phenotypic clues were defined for mutations in ALOX12B, ABCA12, CYP4F22, NIPAL4, SDR9C7 and TGM1, either in neonates or in later life, which allow for greater diagnostic precision. In around 17% of cases, the molecular basis of recessive ichthyosis remains unknown.

WNT10A mutation results in severe tooth agenesis in a family of three sisters.

OBJECTIVES: To identify the genetic basis of severe tooth agenesis in a family of three affected sisters. PATIENTS AND METHODS: A family of three sisters with severe tooth agenesis was recruited for whole-exome sequencing to identify potential genetic variation responsible for this penetrant phenotype. The unaffected father was tested for specific mutations using Sanger sequencing. Gene discovery was supplemented with in situ hybridization to localize gene expression during human tooth development. RESULTS: We report a nonsense heterozygous mutation in exon 2 of WNT10A c.321C>A[p.Cys107*] likely to be responsible for the severe tooth agenesis identified in this family through the creation of a premature stop codon, resulting in truncation of the amino acid sequence and therefore loss of protein function. In situ hybridization showed expression of WNT10A in odontogenic epithelium during the early and late stages of human primary tooth development. CONCLUSIONS: WNT10A has previously been associated with both syndromic and non-syndromic forms of tooth agenesis, and this report further expands our knowledge of genetic variation underlying non-syndromic forms of this condition. We also demonstrate expression of WNT10A in the epithelial compartment of human tooth germs during development.

A genome-wide association study for extremely high intelligence.

We used a case-control genome-wide association (GWA) design with cases consisting of 1238 individuals from the top 0.0003 (~170 mean IQ) of the population distribution of intelligence and 8172 unselected population-based controls. The single-nucleotide polymorphism heritability for the extreme IQ trait was 0.33 (0.02), which is the highest so far for a cognitive phenotype, and significant genome-wide genetic correlations of 0.78 were observed with educational attainment and 0.86 with population IQ. Three variants in locus ADAM12 achieved genome-wide significance, although they did not replicate with published GWA analyses of normal-range IQ or educational attainment. A genome-wide polygenic score constructed from the GWA results accounted for 1.6% of the variance of intelligence in the normal range in an unselected sample of 3414 individuals, which is comparable to the variance explained by GWA studies of intelligence with substantially larger sample sizes. The gene family plexins, members of which are mutated in several monogenic neurodevelopmental disorders, was significantly enriched for associations with high IQ. This study shows the utility of extreme trait selection for genetic study of intelligence and suggests that extremely high intelligence is continuous genetically with normal-range intelligence in the population.

Genetic architecture of acne vulgaris.

Acne vulgaris is a ubiquitary skin disease characterized by chronic inflammation of the pilosebaceous unit resulting from bacterial colonization of hair follicles by Propionibacterium acnes, androgen-induced increased sebum production, altered keratinization and inflammation. Here, we review our current understanding of the genetic architecture of this intriguing disease. We analysed genomewide association studies (GWAS) and candidate genes studies for acne vulgaris. Moreover, we included GWAS studies for the associated disease polycystic ovary syndrome (PCOS). Overall, the available data revealed sixteen genetic loci flagged by single nucleotide polymorphisms (SNPs), none of which has been confirmed yet by independent studies. Moreover, a GWAS for PCOS identified 21 susceptible loci. The genetic architecture is complex which has been revealed by GWAS. Further and larger studies in different populations are required to confirm or disprove results from candidate gene studies as well to identify signals that may overlap between different populations. Finally, studies on rare genetic variants in acne and associated diseases like PCOS may deepen our understanding of its pathogenesis.

Non-syndromic severe hypodontia caused by a novel frameshift insertion mutation in the homeobox of the MSX1 gene.

OBJECTIVE: Inherited congenital anomalies in tooth number, particularly hypodontia are relatively common. Although substantial progress has been made that permits a better understanding of the causes of tooth agenesis, overall knowledge of the phenotype:genotype correlations in this anomaly are still lacking. The aim in this study was to identify the causal gene mutation(s) in a family of two sisters with severe hypodontia (oligodontia) including 2nd premolars and 1st and 3rd molars, using whole exome sequencing (WES). METHODS: WES was performed using in-solution hybridization, followed by massively parallel sequencing. RESULTS: A frameshift insertion of 7 basepairs (GCAAGTT) in the homebox of MSX1 gene located in the exon 2 in heterozygous state has been identified in both sisters (NM_002448:exon2:c.572_573ins GCAAGTT: p.F191fs). CONCLUSION: We conclude that this frameshift mutation in the homeodomain (which plays an essential role in DNA binding) of MSX1 gene is responsible for tooth agenesis in this family. This expands the phenotype-genotype correlation associated with MSX1 mutations.

Social and Financial Outcomes of Living Liver Donation: A Prospective Investigation Within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study 2 (A2ALL-2).

Because results from single-center (mostly kidney) donor studies demonstrate interpersonal relationship and financial strains for some donors, we conducted a liver donor study involving nine centers within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study 2 (A2ALL-2) consortium. Among other initiatives, A2ALL-2 examined the nature of these outcomes following donation. Using validated measures, donors were prospectively surveyed before donation and at 3, 6, 12, and 24 mo after donation. Repeated-measures regression models were used to examine social relationship and financial outcomes over time and to identify relevant predictors. Of 297 eligible donors, 271 (91%) consented and were interviewed at least once. Relationship changes were positive overall across postdonation time points, with nearly one-third reporting improved donor family and spousal or partner relationships and >50% reporting improved recipient relationships. The majority of donors, however, reported cumulative out-of-pocket medical and nonmedical expenses, which were judged burdensome by 44% of donors. Lower income predicted burdensome donation costs. Those who anticipated financial concerns and who held nonprofessional positions before donation were more likely to experience adverse financial outcomes. These data support the need for initiatives to reduce financial burden.

New SMARCA2 mutation in a patient with Nicolaides-Baraitser syndrome and myoclonic astatic epilepsy.

We report a de novo SMARCA2 missense mutation discovered on exome sequencing in a patient with myoclonic astatic epilepsy, leading to reassessment and identification of Nicolaides-Baraitser syndrome. This de novo SMARCA2 missense mutation c.3721C>G, p.Gln1241Glu is the only reported mutation on exon 26 outside the ATPase domain of SMARCA2 to be associated with Nicolaides-Baraitser syndrome and adds to chromatin remodeling as a pathway for epileptogenesis. © 2016 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.

Psychological Outcomes of Living Liver Donors From a Multicenter Prospective Study: Results From the Adult-to-Adult Living Donor Liver Transplantation Cohort Study2 (A2ALL-2).

Although single-center and cross-sectional studies have suggested a modest impact of liver donation on donor psychological well-being, few studies have assessed these outcomes prospectively among a large cohort. We conducted one of the largest, prospective, multicenter studies of psychological outcomes in living liver donors within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study2 (A2ALL-2) consortium. In total, 271 (91%) of 297 eligible donors were interviewed at least once before donation and at 3, 6, 12, and 24 mo after donation using validated measures. We found that living liver donors reported low rates of major depressive (0-3%), alcohol abuse (2-5%), and anxiety syndromes (2-3%) at any given assessment in their first 2 years after donation. Between 4.7% and 9.6% of donors reported impaired mental well-being at various time points. We identified significant predictors for donors' perceptions of being better people and experiencing psychological growth following donation, including age, sex, relationship to recipient, ambivalence and motivation regarding donation, and feeling that donation would make life more worthwhile. Our results highlight the need for close psychosocial monitoring for those donors whose recipients died (n=27); some of those donors experienced guilt and concerns about responsibility. Careful screening and targeted, data-driven follow-up hold promise for optimizing psychological outcomes following this procedure for potentially vulnerable donors.

Acute generalised exanthematous pustulosis (AGEP)-a potential pitfall for the acute physician.

Acute generalised exanthematous pustulosis is a rare drug-induced dermatosis with an incidence of 1-5 cases per million cases per year, characterised by the appearance of hundreds of sterile pustules over erythematous and oedematous skin. Fever and neutrophilia are usually present. It has a rapid course and usually resolves following discontinuation of the precipitating drug or as a result of topical corticosteroid treatment. A patient with AGEP, who presented with generalized pustulosis lesions after the use of Flucloxacillin for cellulitis is described, along with the management and differential diagnosis of this condition.

A genome-wide analysis of putative functional and exonic variation associated with extremely high intelligence.

Although individual differences in intelligence (general cognitive ability) are highly heritable, molecular genetic analyses to date have had limited success in identifying specific loci responsible for its heritability. This study is the first to investigate exome variation in individuals of extremely high intelligence. Under the quantitative genetic model, sampling from the high extreme of the distribution should provide increased power to detect associations. We therefore performed a case-control association analysis with 1409 individuals drawn from the top 0.0003 (IQ >170) of the population distribution of intelligence and 3253 unselected population-based controls. Our analysis focused on putative functional exonic variants assayed on the Illumina HumanExome BeadChip. We did not observe any individual protein-altering variants that are reproducibly associated with extremely high intelligence and within the entire distribution of intelligence. Moreover, no significant associations were found for multiple rare alleles within individual genes. However, analyses using genome-wide similarity between unrelated individuals (genome-wide complex trait analysis) indicate that the genotyped functional protein-altering variation yields a heritability estimate of 17.4% (s.e. 1.7%) based on a liability model. In addition, investigation of nominally significant associations revealed fewer rare alleles associated with extremely high intelligence than would be expected under the null hypothesis. This observation is consistent with the hypothesis that rare functional alleles are more frequently detrimental than beneficial to intelligence.