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.

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.

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.

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.

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.

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.

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.

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.

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.

Whole-exome sequencing diagnosis of two autosomal recessive disorders in one family.

Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous disorder for which subtyping through molecular analysis can help determine the eventual phenotype and prognosis. We used whole-exome sequencing to identify a new homozygous splice-site mutation in ST14 (IVS5+1G>A), encoding matriptase, in a 4-year-old girl with ARCI from a consanguineous Kuwaiti family. Clinically, she also had hypotrichosis, which supported a diagnosis of ARCI type 11. Only four previous examples of pathogenic mutations in ST14 have been reported, and our findings expand the genotype-phenotype correlation for this subtype of ARCI. Our patient was the second child born to these parents; the first (deceased) and third children had congenital brain and eye abnormalities, of uncertain aetiology and with no precise diagnosis. Further analysis of our patient's exome dataset revealed heterozygosity for a splice-site mutation in POMT1 (IVS4+1G>T), encoding the protein O-mannosyltransferase, a gene implicated in Walker-Warburg syndrome. DNA sequencing in the third child showed homozygosity for this mutation in POMT1. The first-cousin parents were both heterozygous for the splice-site mutations in ST14 and POMT1. In this family, whole-exome sequencing provided accurate subtyping of a form of ARCI in one child and provide an explanation for an undiagnosed developmental disorder in two other children, findings that improve the prospects for diagnostic accuracy and genetic counselling, and demonstrate the impact of next-generation sequencing technologies on clinical genetics.

Founder mutation in dystonin-e underlying autosomal recessive epidermolysis bullosa simplex in Kuwait.

Only two homozygous nonsense mutations in the epidermal isoform of the dystonin gene, DST-e, have been reported previously in autosomal recessive epidermolysis bullosa simplex (EBS); the affected pedigrees were Kuwaiti and Iranian. This subtype of EBS is therefore considered to be a rare clinicopathological entity. In this study, we identified four seemingly unrelated Kuwaiti families in which a total of seven individuals had predominantly acral trauma-induced blistering since infancy. All affected individuals were homozygous for the mutation p.Gln1124* in DST-e, the same mutation that was identified in the originally reported family from Kuwait. Haplotype analysis in the five pedigrees (including the previous case) revealed a shared block of ~60 kb of genomic DNA across the site of the mutation, consistent with a founder effect. Most heterozygotes had no clinical abnormalities although one subject had mild transient skin fragility during childhood, an observation noted in the previously reported Iranian pedigree, suggesting that the condition may also be semidominant in some pedigrees rather than purely autosomal recessive. Our study reveals propagation of a mutant ancestral allele in DST-e throughout Kuwait, indicating that this subtype of EBS may be more common in Kuwait, and perhaps other Middle Eastern countries, than is currently appreciated.

Progressive hyperpigmentation in a Taiwanese child due to an inborn error of vitamin B12 metabolism (cblJ).

The physiology of human skin pigmentation is varied and complex, with an extensive melanogenic paracrine network involving mesenchymal and epithelial cells, contributing to the regulation of melanocyte survival and proliferation and melanogenesis. Mutations in several genes, involving predominantly the KIT ligand/c-Kit and Ras/mitogen-activated protein kinase signalling pathways, have been implicated in a spectrum of diseases in which there is hyperpigmentation, hypopigmentation or both. Here, we report on a 12-year-old girl from Taiwan with a 6-year history of diffuse progressive skin hyperpigmentation resulting from a different aetiology: an inborn metabolic disorder of vitamin B12 (cobalamin), designated cblJ. Using whole-exome sequencing we identified a homozygous mutation in ABCD4 (c.423C>G; p.Asn141Lys), which encodes an ATP-binding cassette transporter with a role in the intracellular processing of cobalamin. The patient had biochemical and haematological evidence of cobalamin deficiency but no other clinical abnormalities apart from a slight lightening of her previously black hair. Of note, she had no neurological symptoms or signs. Treatment with oral cobalamin (3 mg daily) led to metabolic correction and some reduction in the skin hyperpigmentation at the 3-month follow-up. This case demonstrates that defects or deficiencies of cobalamin should be remembered in the differential diagnosis of diffuse hyperpigmentary skin disorders.

Whole-exome sequencing improves mutation detection in a diagnostic epidermolysis bullosa laboratory.

BACKGROUND: Subtypes of inherited epidermolysis bullosa (EB) vary significantly in their clinical presentation and prognosis. Establishing an accurate diagnosis is important for genetic counselling and patient management. Current approaches in EB diagnostics involve skin biopsy for immunohistochemistry and transmission electron microscopy, and Sanger sequencing of candidate genes. Although informative in most cases, this approach can be expensive and laborious and may fail to identify pathogenic mutations in ~15% of cases. OBJECTIVES: Next-generation DNA sequencing (NGS) technologies offer a fast and efficient complementary diagnostic strategy, but the value of NGS in EB diagnostics has yet to be explored. The aim of this study was to undertake whole-exome sequencing (WES) in nine cases of EB in which established diagnostic methods failed to make a genetic diagnosis. METHODS: Whole-exome capture was performed using genomic DNA from each case of EB, followed by massively parallel sequencing. Resulting reads were mapped to the human genome reference hg19. Potentially pathogenic mutations were subsequently confirmed by Sanger sequencing. RESULTS: Analysis of WES data disclosed biallelic pathogenic mutations in each case, with all mutations occurring in known EB genes (LAMB3, PLEC, FERMT1 and COL7A1). This study demonstrates that NGS can improve diagnostic sensitivity in EB compared with current laboratory practice. CONCLUSIONS: With appropriate diagnostic platforms and bioinformatics support, WES is likely to increase mutation detection in cases of EB and improve EB diagnostic services, although skin biopsy remains an important diagnostic investigation in current clinical practice.

The interpretation and management of abnormal liver function tests.

Liver function tests (LFTs) are frequently requested as part of routine health assessments on serving members of the Royal Navy (RN). In common with many investigations there are a number of abnormal results in healthy individuals (0.5 - 9% depending on test and study population). There are established patterns of LFT derangement such as cholestatic derangement, hepatocellular derangement, and failure of synthetic function. There can be indicators to the cause of the derangement by assessing the ratios of elevated assays in relation to one another. This article aims to address the definition, potential causes and further investigation of common patterns of LFT derangement found in primary care in the RN.

Germline CDH1 mutations in bilateral lobular carcinoma in situ.

BACKGROUND: Invasive lobular breast cancer (ILC) and lobular carcinoma in situ (LCIS) are characterised by loss of E-cadherin expression. However germline CDH1 mutations are rare in cases of ILC with no family history of hereditary diffuse gastric cancer (HDGC) and have not been described in women with LCIS. METHODS: We screened the CDH1 gene in 50 cases of bilateral LCIS/ILC using Sanger sequencing and MLPA. RESULTS: Sanger sequencing revealed four pathogenic germline mutations, including a novel splicing mutation (c.48+1G>A). The remaining three (c.1465insC, c.1942G>T, c.2398delC) have been previously described. All four cases had bilateral LCIS +/- ILC and no family history of gastric cancer. CONCLUSION: CDH1 germline mutations have not been previously described in women with LCIS. We have shown that germline CDH1 mutations are associated with early onset of bilateral LCIS with or without ILC in women without a family history of gastric cancer. CDH1 mutation screening should be considered in women with early onset of bilateral LCIS/ILC with no family history of HDGC.