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Context: The syndrome of adrenal insufficiency, obesity, and red hair is a rare autosomal recessive disorder. The majority of disease-causing variants associated with the syndrome are located in the coding region of the POMC gene. Objective: This work describes 7 unrelated patients who shared a novel homozygous mutation in the 5′-untranslated region (UTR) of the POMC gene and functionally characterize this novel variant. Methods: Whole-exome sequencing (WES) with autozygosity mapping, Sanger sequencing, model expression system studies, and RNA sequencing were used for identification of the disease-causing variant and its subsequent functional characterization. Seven unrelated patients of the Perm Tatar ethnic group presented with hypoglycemia and excessive weight gain, low plasma adrenocorticotropin, and cortisol. Five of 7 children had red hair; 6 of 7 patients also showed signs of bronchial obstruction. Results: WES showed shared autozygosity regions overlapping the POMC gene. Sanger sequencing of the POMC 5′-UTR detected a homozygous variant chr2:25391366C >T (hg19) at the splice donor site of intron 1. As demonstrated by the model expression system, the variant led to a significant decrease in the POMC messenger RNA level. Analyses of the patients’ haplotypes were suggestive of the founder effect. We estimate that the mutation must have occurred at least 4.27 generations ago (95% CI, 0.86-7.67). Conclusion: This report presents a new molecular mechanism of POMC deficiency and contributes to the information on phenotypic variability in patients with this disorder. [ABSTRACT FROM AUTHOR]

FUNDING: NICHD IRP to JCM DISCLOSURES: The author declared no competing interests OC9 Bone cell functions in peptidylprolyl cis-trans isomerase B (PPIB) knock-out mouse model for type IX osteogenesis imperfecta (OI) are distinct from classical dominant OI Ying Liu 1, Theresa Hefferan 2, Nadja Fratzl-Zelman 3, Joan Marini 1 1 Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States, 2 Biomaterials and Histomorphometry Core Laboratory, Mayo Clinic Rochester, MN., Rochester, United States, 3 Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria Osteogenesis imperfecta (OI) is a genetically heterogeneous bone fragility disorder. DISCLOSURES: The author declared no competing interests P4 Studies of OI patient and murine osteoblasts to investigate phenotypic variability of dominant osteogenesis imperfecta Milena Jovanovic 1, Apratim Mitra 2, Chris Stephan 3, Kenneth Kozloff 3, Ryan K Dale 2, Joan C Marini 1 1 Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States, 2 Bioinformatics and Scientific Programming Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States, 3 Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, United States Osteogenesis Imperfecta (OI) is a heterogeneous bone disorder characterized by bone fractures, growth deficiency and skeletal defects. [Extracted from the article]

Background Pathological features of autosomal dominant polycystic kidney disease (ADPKD) include enlarged kidney volume, higher frequency of digestive diverticulitis and abdominal wall hernias. Therefore, many nephrologists have concerns about the use of peritoneal dialysis (PD) in ADPKD patients. We aimed to analyse survival and technique failure in ADPKD patients treated with PD. Methods We conducted two retrospective studies on patients starting dialysis between 2000 and 2010. We used two French registries: the French Renal Epidemiology and Information Network (REIN) and the French language Peritoneal Dialysis Registry (RDPLF). Using the REIN registry, we compared the clinical features and outcomes of ADPKD patients on PD (n  = 638) with those of ADPKD patients on haemodialysis (HD) (n  = 4653); with the RDPLF registry, those same parameters were determined for ADPKD patients on PD (n = 797) and compared with those of non-ADPKD patients on PD (n = 12 059). Results A total of 5291 ADPKD patients and 12 059 non-ADPKD patients were included. Analysis of the REIN registry found that ADPKD patients treated with PD represented 10.91% of the ADPKD population. During the study period, PD was used for 11.2% of the non-ADPKD population. Compared with ADPKD patients on HD, ADPKD patients on PD had higher serum albumin levels (38.8 ± 5.3 versus 36.8 ± 5.7 g/dL, P < 0.0001) and were less frequently diabetic (5.31 versus 7.71%, P < 0.03). The use of PD in ADPKD patients was positively associated with the occurrence of a kidney transplantation but not with death [hazard ratio 1.15 (95% confidence interval 0.84–1.58)]. Analysis of the RDPLF registry found that compared with non-ADPKD patients on PD, ADPKD patients on PD were younger and had fewer comorbidities and better survival. ADPKD status was not associated with an increased risk of technique failure or an increased risk of peritonitis. Conclusions According to our results, PD is proposed to a selected population of ADPKD patients, PD does not have a negative impact on ADPKD patients' overall survival and PD technique failure is not influenced by ADPKD status. Therefore PD is a reasonable option for ADPKD patients. [ABSTRACT FROM AUTHOR]

A forensic validation study of the Early Access Huaxia™ Platinum Polymerase Chain Reaction (PCR) kit was completed to document the performance capabilities and limitations. The genotyping of DNA samples was consistent across a large range of template DNA concentrations, with complete profiles obtained at 0.125 ng; however, no more than 2 mm × 1.2 mm punches of samples would be recommended for direct amplification. The size precision and accuracy test revealed the genotyping ability; while consistent results were obtained when comparing the kit with other commercially available systems. In addition, the whole PCR amplification can finish within approximately 45 min, making the system suitable for fast-detection. However, only partial profiles may be obtained with challenging samples, including DNA stored on Foam-Tipped Applicators (FTA) cards or some case samples. For the forensic application in ethnic groups, a total of 282 and 229 alleles were obtained in Han and Mongolia, respectively. Since the 23 short tandem repeats were independent from each other, the cumulative power of exclusion in duos was 0.999 999 157 188 and the cumulative power of exclusion in trios was 0.999 999 999 859 in the Han group while the cumulative power of exclusion in duos (CPEduo) was 0.999 998 848 26 and cumulative power of exclusion in trios (CPEtrio) was 0.999 999 999 79 in the Mongolia group. And good internal consistency was found between the two investigated groups and the Sichuan Han, Hui, Tibetan and Uygur according to available reference data. [ABSTRACT FROM AUTHOR]

Background: Poorer self-rated health (SRH) predicts worse health outcomes, even when adjusted for objective measures of disease at time of rating. Twin studies indicate SRH has a heritability of up to 60% and that its genetic architecture may overlap with that of personality and cognition.Methods: We carried out a genome-wide association study (GWAS) of SRH on 111 749 members of the UK Biobank sample. Univariate genome-wide complex trait analysis (GCTA)-GREML analyses were used to estimate the proportion of variance explained by all common autosomal single nucleotide polymorphisms (SNPs) for SRH. Linkage disequilibrium (LD) score regression and polygenic risk scoring, two complementary methods, were used to investigate pleiotropy between SRH in the UK Biobank and up to 21 health-related and personality and cognitive traits from published GWAS consortia.Results: The GWAS identified 13 independent signals associated with SRH, including several in regions previously associated with diseases or disease-related traits. The strongest signal was on chromosome 2 (rs2360675, P = 1.77 x 10 -10 ) close to KLF7 . A second strong peak was identified on chromosome 6 in the major histocompatibility region (rs76380179, P = 6.15 x 10 -10 ). The proportion of variance in SRH that was explained by all common genetic variants was 13%. Polygenic scores for the following traits and disorders were associated with SRH: cognitive ability, education, neuroticism, body mass index (BMI), longevity, attention-deficit hyperactivity disorder (ADHD), major depressive disorder, schizophrenia, lung function, blood pressure, coronary artery disease, large vessel disease stroke and type 2 diabetes.Conclusions: Individual differences in how people respond to a single item on SRH are partly explained by their genetic propensity to many common psychiatric and physical disorders and psychological traits. [ABSTRACT FROM AUTHOR]

Background. Renal imaging examinations provide high-resolution information about the anatomic structure of the kidneys and are used to measure total kidney volume (TKV) in autosomal dominant polycystic kidney disease (ADPKD) patients. TKV has become the gold-standard image biomarker for ADPKD progression at early stages of the disease and is used in clinical trials to characterize treatment efficacy. Automated methods to segment the kidneys and measure TKV are desirable because of the long time requirement for manual approaches such as stereology or planimetry tracings. However, ADPKD kidney segmentation is complicated by a number of factors, including irregular kidney shapes and variable tissue signal at the kidney borders. Methods.We describe an image processing approach that overcomes these problems by using a baseline segmentation initialization to provide automatic segmentation of follow-up scans obtained years apart. We validated our approach using 20 patients with complete baseline and follow-up T1-weighted magnetic resonance images. Both manual tracing and stereology were used to calculate TKV, with two observers performing manual tracings and one observer performing repeat tracings. Linear correlation and Bland-Altman analysis were performed to compare the different approaches. Results. Our automated approach measured TKV at a level of accuracy (mean difference ± standard error = 0.99 ± 0.79%) on par with both intraobserver (0.77 ± 0.46%) and interobserver variability (1.34 ± 0.70%) of manual tracings. All approaches had excellent agreement and compared favorably with ground-truth manual tracing with interobserver, stereological and automated approaches having 95% confidence intervals ∼±100 mL. Conclusions. Our method enables fast, cost-effective and reproducible quantification of ADPKD progression that will facilitate and lower the costs of clinical trials in ADPKD and other disorders requiring accurate, longitudinal kidney quantification. In addition, it will hasten the routine use of TKV as a prognostic biomarker in ADPKD. [ABSTRACT FROM AUTHOR]

Background Autosomal recessive congenital ichthyosis ( ARCI) is a heterogeneous group of diseases of keratinization, characterized primarily by abnormal skin scaling over the whole body surface. Recently, ARCI has been designated to include the major forms of lamellar ichthyosis ( LI), congenital ichthyosiform erythroderma ( CIE) and harlequin ichthyosis. The first two conditions are the most common major clinical subtypes, and both are caused principally by mutations in the transglutaminase 1 gene, TGM1, although other genes may be responsible in some cases. Aim To identify the genetic mutations underlying LI in a Chinese family with LI, and to review all the known TGM1 mutations in Chinese patients with ARCI. Methods The proband had the severe classic LI phenotype, and was a member of a four-generation family with close blood relationships. We sequenced the DNA of the patients and close relatives. We also reviewed 13 Chinese patients with ARCI from 8 reported families, comprising 10 patients with LI, 2 with CIE and 1 with bathing suit ichthyosis. Results We characterized 14 different TGM1 mutations. Six of these were reported in other ethnic groups initially and later in Chinese patients, while the remaining eight were first described in Chinese patients. Of the latter, five have been reported only in Chinese patients, while the remaining three have also been reported in other ethnic groups. Conclusion This study expands the current spectrum on TGM1 mutation and increases the knowledge of TGM1 mutation characteristics. [ABSTRACT FROM AUTHOR]

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis is an autosomal-recessive disease caused by mutations in the CLDN16 or CLDN19 genes, which encode tight junction-associated proteins, claudin-16 and -19. The resultant tubulopathy leads to urinary loss of Mg2+ and Ca2+, with subsequent nephrocalcinosis and end-stage renal disease (ESRD). An 18-year-old boy presented with chronic kidney disease and proteinuria, as well as hypomagnesaemia, hypercalciuria and nephrocalcinosis. A kidney biopsy revealed tubular atrophy, interstitial fibrosis and segmental sclerosis of some glomeruli. Two novel mutations in the CLDN16 gene were identified: c.340C>T (nonsense) and c.427+5G>A (splice site). The patient reached ESRD at 23 and benefited from kidney transplantation. [ABSTRACT FROM AUTHOR]

In France gamete donation and notably sperm donation are anonymous. It has been claimed that anonymous artificial insemination by donor (AID) could highly contribute to an increase in the level of consanguinity and the incidence of autosomal recessive diseases, due to the unions between offspring of anonymous donors, unaware of their biological kinship, with the special case of unions between half-siblings. The actual incidence of consanguinity due to AID was compared with that resulting from the two other main sources of consanguinity and recessive diseases, i.e. voluntary unions between related individuals or inadvertent unions between the offspring of a common unknown male ancestor (false paternity). From these data, we estimated that expected unions in France between half sibs per year are 0.12 between offspring of sperm donors (1.2 every 10 years) and 0.5 between offspring of common male ancestors through false paternity (5 every 10 years). More generally, the inadvertent unions between false paternity offspring are roughly four times more frequent than those resulting from anonymous AID. We estimated that in the future, when AID has been in practice for several generations, out the 820 000 annual births in France, respectively, 6 and 25 births will be consanguineous through an unknown common ancestor related to anonymous AID and to a false paternity, both of which are negligible when compared with the 1256 children born from first-degree cousins. About 672 children per year are born with a recessive genetic disease due to the panmictic risk and additional affected cases due to consanguinity would be 34.54 for first-cousin offspring, 0.33 for offspring of individuals related due to false paternity and 0.079 for offspring of individuals related due to anonymous AID. Anonymous AID would therefore be responsible for 0.46% of consanguineous births and for 0.01% of recessive diseases. Therefore, the effect of anonymous AID on half-sibling unions, consanguinity and recessive disease incidence can be regarded as marginal. [ABSTRACT FROM AUTHOR]

Several different genes have been implicated in the pathophysiology of inherited blistering skin diseases. Recently, autosomal recessive loss-of-function mutations in EXPH5 (encoding exophilin-5, also known as Slac2-b, a protein involved in intracellular vesicle transport) were identified in a new mechanobullous disease resembling a form of epidermolysis bullosa simplex ( EBS). Here, we searched for mutations in EXPH5 in a 4-year-old white boy with EBS in whom initial Sanger sequencing of known genes implicated in intraepidermal skin fragility failed to identify pathogenic mutations. Transmission electron microscopy of rubbed nonlesional patient skin revealed disruption of keratinocytes in the lower epidermis with cytolysis and acantholysis, keratin filament clumping and prominent perinuclear cytoplasmic vesicles, and provided the clue to the candidate gene pathology. Sanger sequencing of genomic DNA showed compound heterozygosity for two new mutations in EXPH5, c.1947dupC (p.Pro649fsPro*11) and c.2249C>A (p.Ser750*). Immunofluorescence microscopy of patient skin showed a complete absence of exophilin-5 labelling. This case represents the third pedigree with EXPH5 mutations resulting in inherited skin fragility. The clinical and molecular data expand genotype-phenotype correlation in this new form of EBS and demonstrate the important role of exophilin-5 in keratinocyte cell biology. [ABSTRACT FROM AUTHOR]

The article presents a cohort study of Italian and Portuguese patients with autosomal recessive congenital ichtyosis (ARCI), defined as a group of heterogeneous cornification disease. It is inferred that about 30-50% if ARCI patients have transglutaminase 1 deficiency due to mutations in TGM1 genes. TGM1 molecular analysis was used in the study. The prevalence of ARCI in Europe is discussed.

Purpose Surgical management of autosomal dominant polycystic kidney disease (ADPKD) in patients awaiting renal transplantation is a challenging task. Methods From 1998 to 2009, a total of 100 consecutive renal transplantations with simultaneous unilateral nephrectomy were performed in 59 men and 41 women with ADPKD and end-stage renal failure. About 38% received kidney allografts from living donors. The ipsilateral polycystic kidney was removed at the time of renal transplantation. Immunosuppressive therapy was not modified. Cold ischaemia time was 155 (38–204 min) versus 910 min (95–2760 min) for living versus deceased donor transplantation. Mean weight of removed kidneys was 2002 g (414–8850 g). Mean follow-up was 3.0 years (0.8–10.0 years). Results Overall patient and graft survival were 97 and 96% at 1 year and 93 and 80% at 5 years, respectively. Serum creatinine at current follow-up was 1.49 (0.8–2.8) mg/dL. Surgical complications, which might be associated with simultaneous nephrectomy requiring re-operation, occurred in 12% (lymphocele 4%, hernia 4%, post-operative haematoma or bleeding 4%). None of the patients died peri-operatively. Conclusion Renal transplantation with simultaneous unilateral nephrectomy in ADPKD is a reasonable procedure for patients suffering from massively enlarged native kidneys. [ABSTRACT FROM AUTHOR]

It is clinically useful to distinguish between two types of hereditary nephrogenic diabetes insipidus (NDI): a ‘pure’ type characterized by loss of water only and a complex type characterized by loss of water and ions. Patients with congenital NDI bearing mutations in the vasopressin 2 receptor gene, AVPR2, or in the aquaporin-2 gene, AQP2, have a pure NDI phenotype with loss of water but normal conservation of sodium, potassium, chloride and calcium. Patients with hereditary hypokalemic salt-losing tubulopathies have a complex phenotype with loss of water and ions. They have polyhydramnios, hypercalciuria and hypo- or isosthenuria and were found to bear KCNJ1 (ROMK) and SLC12A1 (NKCC2) mutations. Patients with polyhydramnios, profound polyuria, hyponatremia, hypochloremia, metabolic alkalosis and sensorineural deafness were found to bear BSND mutations. These clinical phenotypes demonstrate the critical importance of the proteins ROMK, NKCC2 and Barttin to transfer NaCl in the medullary interstitium and thereby to generate, together with urea, a hypertonic milieu. This editorial describes two new developments: (i) the genomic information provided by the sequencing of the AQP2 gene is key to the routine care of these patients, and, as in other genetic diseases, reduces health costs and provides psychological benefits to patients and families and (ii) the expression of AQP2 mutants in Xenopus oocytes and in polarized renal tubular cells recapitulates the clinical phenotypes and reveals a continuum from severe loss of function with urinary osmolalities <150 mOsm/kg H2O to milder defects with urine osmolalities >200 mOsm/kg H2O. [ABSTRACT FROM PUBLISHER]

Background: Pendred syndrome is a rare autosomal recessive condition, characterized by functional impairment of thyroid gland and sensorineural hearing loss. The syndrome presents in patients with homozygous or compound heterozygous mutation. The presentation in the form of neck mass in a newborn is rare.Case Characteristics: A 1 month old baby presented to us with neck mass, which was found to be an enlarged thyroid gland. Thyroid function tests were consistent with hypothyroidism. Further evaluation revealed moderate sensorineural hearing loss; genetic analysis showed that baby was homozygous for the known mutations causing the disease.Intervention: Thyroid hormone replacement and hearing habilitation were done. Follow up showed regression of the neck mass and normalization of thyroid function tests. Genetic counseling of the family was done.Message: Identification of the exact cause of congenital hypothyroidism can prevent grave consequences later on for the patient as well as for the family. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 8-year-old girl was under the care of dermatology with congenital ichthyosis and hypotonia and mild dysmorphic features led to a clinical diagnosis of Prader–Willi syndrome (PWS) in infancy. It mentions causes are a deletion of the paternal allele or maternal uniparental disomy (UPD) and compatible with an autosomal recessive congenital ichthyosis (ARCI). It also mentions methylation-specific polymerase chain reaction analysis at locus on chromosome.

Albumin, a serum transport protein, provides 80% of colloid osmotic pressure. Congenital analbuminemia (CAA) is an autosomal recessive disorder characterized by absence of serum albumin. Fifty cases of CAA have been reported throughout the world; however, little is known about its clinical impact. Most reported cases have few clinical signs and symptoms. Twelve local cases from the northwestern central plains region in Saskatchewan were identified and reviewed to ascertain morbidity and mortality related to CAA. All of the cases were from two remote First Nations communities. Cases had frequent hospital admissions and recurrent respiratory tract infections. Placental abnormalities included hydropic placentas, placental infarcts and microcalcifications. One-half of the cases were born preterm and one-quarter were small for their gestational age. There were three mortalities in the case series. The present case series suggests increased morbidity and mortality during infancy in patients with CAA. The long-term risks of CAA in this population are unknown and a longitudinal study is recommended. [ABSTRACT FROM AUTHOR]