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In recent decades, thyroid cancer (TC) has become one of the most common endocrine malignancies. Next-generation sequencing of paired TC and adjacent healthy thyroid tissues demonstrated that polycystic kidney and hepatic disease 1-like 1 (PKHD1L1) may serve as a tumour suppressor gene in thyroid cancer. However, the function of PKHD1L1 in thyroid cancer is still unknown. To validate the results of whole-transcriptome resequencing, the expression levels of PKHD1L1 were evaluated in 58 pairs of papillary thyroid cancer (PTC) tissue samples and three thyroid cancer cell lines. In addition, The Cancer Genome Atlas (TCGA) data were used to analyse the relationship between PKHD1L1 and patient clinicopathological features. Cell Counting Kit-8, colony formation, migration and invasion assays were performed to assess the effects of PKHD1L1 knockdown in three TC cell lines. PKHD1L1 expression was significantly lower in thyroid carcinoma compared with that in matched normal tissue, and this result was consistent with that in TCGA cohort. TCGA data demonstrated that PKHD1L1 downregulation was associated with a number of aggressive clinicopathological features, such as histological type, lymph node metastasis (LNM), distant metastasis, tumour size and clinical stage. Logistic regression analysis of data from patients with PTC revealed that PKHD1L1 expression, histological type, age and tumour size were independent high-risk factors for LNM. The PKHD1L1 biological function was investigated in the three TC cell lines: TPC-1, KTC1 and BCPAP. A loss of function experiment demonstrated that PKHD1L1 knockdown promoted cell proliferation, colony formation and cell invasion in TC cell lines. In conclusion, PKHD1L1 may be a tumour suppressor gene associated with PC, and may be a potential therapeutic target in the future. [ABSTRACT FROM AUTHOR]

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease. This pathology has been increasingly diagnosed in utero and several sonographic patterns are well described in the literature.Objective: To present a series of fetuses with an unusual imaging pattern of ADPKD, mimicking autosomal recessive polycystic kidney disease (ARPKD).Materials and Methods: We retrospectively reviewed second-line ultrasound (US) scans performed for suspicion of fetal kidney pathology between 2006 and 2018. Inclusion criteria were (1) proven ADPKD on the basis of a known family history and/or of genetic testing and (2) US features suggestive of ARPKD. We recorded the clinical, imaging, genetic and pathological findings in cases with pregnancy termination.Results: Three out of 12 patients with proven ADPKD diagnosed in utero presented with US features suggestive of ARPKD. Furthermore, an additional patient observed at another institution was added to the series. History of familial ADPKD was present in three cases. US showed enlarged kidneys with increased cortical echogenicity, decreased corticomedullary differentiation, multiple medullary cysts and decreased amniotic fluid in all four cases. Pregnancy was terminated in two cases (histology confirmed features in keeping with ADPKD), one premature neonate died (histology in progress) and one child is alive. Genetic testing showed a homozygous mutation of the PKD1 gene in two patients, a heterozygous mutation of the PKD1 gene in one patient and was not performed in the remaining patient.Conclusion: This series describes an unusual sonographic prenatal presentation of ADPKD, not yet well described in the radiologic literature, mimicking ARPKD. [ABSTRACT FROM AUTHOR]

Osteopetrosis refers to a group of rare genetic bone diseases that are clinically characterized by increased bone mass and fragility. The principal pathogenic defect in patients with chloride channel 7 (CLCN7) gene-dependent osteopetrosis is reduced osteoclast activity, which leads to decreased bone resorption. Mutations in the CLCN7 gene result in autosomal dominant osteopetrosis type II (ADO-II), autosomal recessive osteopetrosis (ARO) and intermediate ARO (IARO). In the present study, eight mutations in the CLCN7 gene were identified in six patients with familial osteopetrosis and one patient with sporadic osteopetrosis. Heterozygous mutations c.856C>T (R286W), c.2236T>G (Y746D), c.296A>G (Y99C) and c.937G>A (E313K), and a splice mutation (c.2232-2A>G) in the CLCN7 gene were detected in patients with ADO-II. A homozygous mutation c.2377G>C (G793R), and a compound heterozygous mutation c.1409C>T (P470L) and c.647_648dupTG (K217X) were detected in two Chinese families with IARO. Among these mutations, two heterozygous mutations (c.2236T>G and c.2232-2A>G), one homozygous mutation (c.2377G>C) and the compound heterozygous mutation (c.1409C>T and c.647_648dupTG) are novel, to the best of our knowledge. The present findings not only broaden the allelic spectrum of CLCN7 mutations, but also provide increased knowledge of the clinical phenotypes observed in Chinese patients with osteopetrosis. [ABSTRACT FROM AUTHOR]

Autosomal recessive cornea plana is a very rare hereditary ocular disease, characterized by a flattened corneal curvature, marked hyperopia due to low refractive power and frequently consequent accommodative esotropia. Other features include various cornea anterior segment abnormalities, without systemic problems. The purpose of the present study was to investigate the clinical and molecular alterations in a Chinese family with cornea plana. Full ophthalmic examinations of the patients were performed, including slit-lamp examination, fundus examination and ocular ultrasound. Whole-exome sequencing data were screened for pathological variants in the proband, which were confirmed by Sanger sequencing. One novel missense mutation, c.242A>G (p.N81S) and another novel 7 base-pair deletion mutation, c.772-779del (p.G258Cfs*30), were detected in the keratocan (KERA) gene; two affected siblings inherited these variations in a compound heterozygous state, which were derived from the clinically unaffected heterozygous father (c.772_779del) and mother (c.242A>G), respectively. Neither mutation was observed in unrelated healthy controls (n=200). Multiple computer software predictions supported the pathogenicity of the two variants. Furthermore, protein modeling prediction was performed to better understand the molecular basis of cornea plana, particularly the importance of the leucine-rich repeat domain. This study presents the 14th pathogenic KERA mutations identified worldwide and the first in East Asia so far, to the best of our knowledge. These findings guided prenatal diagnosis for the family in question and expand on the variant spectrum of KERA, therefore facilitating genetic counseling. [ABSTRACT FROM AUTHOR]

Objective: To compare diffusion tensor imaging (DTI) of the kidneys and its derived parameters in children with autosomal recessive polycystic kidney disease (ARPKD) versus healthy controls. Methods: In a prospective IRB-approved study, we evaluated the use of DTI to compare kidney parenchyma FA values in healthy controls (age-matched children with no history of renal disease) versus patients with ARPKD. A 20-direction DTI with b-values of b = 0 s/mm2 and b = 400 s/mm2 was used to acquire data in coronal direction using a fat-suppressed spin-echo echo-planar sequence. Diffusion Toolkit and TrackVis were used for analysis and segmentation. TrackVis was used to draw regions of interest (ROIs) covering the entire volume of the renal parenchyma, excluding the collecting system. Fibers were reconstructed using a deterministic fiber tracking algorithm. The FA values based on the ROI data, mean length, and volume of the tracks based on the fiber tracking data were recorded. Results: Eight healthy controls (mean age = 12.9 years ± 4.0; 1/8 males) and six ARPKD participants (mean age = 13.8 years ± 8.5; 5/6 males) were included in the study. Compared to healthy controls, patients with ARPKD had significantly lower FA values (0.33 ± 0.03 vs. 0.25 ± 0.02, p = 0.002) and mean track length (16.73 ± 3.43 vs. 11.61 ± 1.29 mm, p = 0.005). Conclusion: DTI of the kidneys shows significantly lower FA values and mean track length in children and young adults with ARPKD compared to normal subjects. DTI of the kidney offers a novel approach for characterizing renal disease based on changes in diffusion anisotropy and kidney structure. [ABSTRACT FROM AUTHOR]

Heterozygosity for human polycystic kidney and hepatic disease 1 (PKHD1) mutations was recently associated with cystic liver disease and radiographic findings resembling medullary sponge kidney (MSK). However, the relevance of these associations has been tempered by a lack of cystic liver or renal disease in heterozygous mice carrying Pkhd1 gene trap or exon deletions. To determine whether heterozygosity for a smaller Pkhd1 defect can trigger cystic renal disease in mice, we generated and characterized mice with the predicted truncating Pkhd1C642** mutation in a region corresponding to the middle of exon 20 cluster of five truncating human mutations (between PKHD1G617fs and PKHD1G644*). Mouse heterozygotes or homozygotes for the Pkhd1C642** mutation did not have noticeable liver or renal abnormalities on magnetic resonance images during their first weeks of life. However, when aged to ~1.5 yr, the Pkhd1C642** heterozygotes developed prominent cystic liver changes; tissue analyses revealed biliary cysts and increased number of bile ducts without signs of congenital hepatic fibrosis-like portal field inflammation and fibrosis that was seen in Pkhd1C642** homozygotes. Interestingly, aged female Pkhd1C642** heterozygotes, as well as homozygotes, developed radiographic changes resembling MSK. However, these changes correspond to proximal tubule ectasia, not an MSK-associated collecting duct ectasia. In summary, by demonstrating that cystic liver and kidney abnormalities are triggered by heterozygosity for the Pkhd1C642** mutation, we provide important validation for relevant human association studies. Together, these investigations indicate that PKHD1 mutation heterozygosity (predicted frequency 1 in 70 individuals) is an important underlying cause of cystic liver disorders and MSK-like manifestations in a human population. [ABSTRACT FROM AUTHOR]

Deficiency in polycystin 1 triggers specific changes in energy metabolism. To determine whether defects in other human cystoproteins have similar effects, we studied extracellular acidification and glucose metabolism in human embryonic kidney (HEK-293) cell lines with polycystic kidney and hepatic disease 1 (PKHD1) and polycystic kidney disease (PKD) 2 (PKD2) truncating defects along multiple sites of truncating mutations found in patients with autosomal recessive and dominant PKDs. While neither the PKHD1 or PKD2 gene mutations nor their position enhanced cell proliferation rate in our cell line models, truncating mutations in these genes progressively increased overall extracellular acidification over time (P < 0.001 for PKHD1 and PKD2 mutations). PKHD1 mutations increased nonglycolytic acidification rate (1.19 vs. 1.03, P < 0.002), consistent with an increase in tricarboxylic acid cycle activity or breakdown of intracellular glycogen. In addition, they increased basal and ATP-linked oxygen consumption rates [7.59 vs. 5.42 (P < 0.015) and 4.55 vs. 2.98 (P < 0.004)]. The PKHD1 and PKD2 mutations also altered mitochondrial morphology, resembling the effects of polycystin 1 deficiency. Together, these data suggest that defects in major PKD genes trigger changes in mitochondrial energy metabolism. After validation in in vivo models, these initial observations would indicate potential benefits of targeting energy metabolism in the treatment of PKDs. [ABSTRACT FROM AUTHOR]

Introduction: DNA testing for autosomal recessive disease mutations in many dog breeds is now relatively commonplace. There have, however, been few efforts made to determine changes in the frequency of disease causing mutations as a result of probable selection based on the results of DNA testing. This study makes use of genotype data from both DNA test results reported to the UK Kennel Club and where known from a ‘hereditary status’ (where a definitive genotype may be inferred and ascribed based on known parental genotypes) to do so. Results: The results, using all known genotype data, show a general and sizeable decline in disease causing mutation frequency across eight diseases in eight breeds (by between 12–86% in dogs born 2–4 years after publication of the mutation, and by nearly 90% or more in those born 8–10 years after). In contrast, data from test results only, while revealing an almost complete and immediate end to the production of affected individuals, show little general decline in either the derived mutation frequency or the proportion of heterozygote carriers. It appears that the numerical size of the breed is an important determinant on the rate of uptake of a DNA test (as judged by the proportion of a breed born four years after publication of the disease-causing mutation with a known genotype). Conclusion: These results show that dog breeders appear to be incorporating the results of DNA testing into their selection strategies to successfully decrease the frequency of the mutation. It is shown that use of DNA test result data alone does not reveal such trends, possibly as some breeders undertake testing to determine clear stock which can then be used to produce future disease-free generations in the knowledge they are not carrying the disease causing mutation. [ABSTRACT FROM AUTHOR]

Background & Aims: Wilson's disease (WD) is an autosomal recessive disorder associated with disease‐causing alterations across the ATP7B gene, with highly variable symptoms and age of onset. We aimed to assess whether the clinical variability of WD relates to modifier genes. Methods: A total of 248 WD patients were included, of whom 148 were diagnosed after age of 17. Human exome libraries were constructed using AmpliSeq technology and sequenced using the IonProton platform. Results: ATP7B p.His1069Gln mutation was present in 215 patients, with 112 homozygotes and 103 heterozygotes. Three other mutations: p.Gln1351Ter, p.Trp779Ter and c.3402delC were identified in >10 patients. Among patients, 117 had a homozygous mutation, 101 were compound heterozygotes, 27 had one heterozygous mutation, and 3 other patients had no identifiable pathogenic variant of ATP7B. Sixteen mutations were novel, found as part of a compound mutation or as a sole, homozygous mutation. For disease phenotype prediction, age at diagnosis was a deciding factor, while frameshift allelic variants of ATP7B and being male increased the odds of developing a neurological phenotype. Rare allelic variants in ESD and INO80 increased and decreased chances for the neurological phenotype, respectively, while rare variants in APOE and MBD6 decreased the chances of WD early manifestation. Compound mutations contributed to earlier age of onset. Conclusions: In a Polish population, genetic screening for WD may help genotype for four variants (p.His1069Gln, p.Gln1351Ter, p.Trp779Ter and c.3402delC), with direct sequencing of all ATP7B amplicons as a second diagnostic step. We also identified some allelic variants that may modify a WD phenotype. [ABSTRACT FROM AUTHOR]

Background: Hypomagnesaemia is present in 40-50% of children with autosomal dominant renal cysts and diabetes syndrome (RCAD). On the contrary, the prevalence of hypomagnesaemia in children with autosomal dominant polycystic kidney disease (ADPKD) has never been examined. We aimed to investigate whether hypomagnesaemia is present in children with polycystic kidney diseases.Methods: Children with cystic kidney diseases were investigated in a cross-sectional study. Serum concentrations of magnesium (S-Mg) and fractional excretion of magnesium (FE-Mg) were tested. Fifty-four children with ADPKD ( n = 26), autosomal recessive polycystic kidney disease (ARPKD) ( n = 16) and RCAD ( n = 12) with median age of 11.2 (0.6-18.6) years were investigated.Results: Hypomagnesaemia (S-Mg < 0.7 mmol/L) was detected in none of the children with ADPKD/ARPKD and in eight children (67%) with RCAD. Median S-Mg in children with ADPKD/ARPKD was significantly higher than in children with RCAD (0.89 vs. 0.65 mmol/L, P < 0.01). The FE-Mg was increased in 23% of patients with ADPKD/ARPKD (all had chronic kidney disease stages 2-4) and in 63% of patients with RCAD, where it significantly correlated with estimated glomerular filtration rate (r = -0.87, P < 0.01).Conclusions: Hypomagnesaemia is absent in children with ADPKD or ARPKD and could serve as a marker for differential diagnostics between ADPKD, ARPKD and RCAD in children with cystic kidney diseases of unknown origin where molecular genetic testing is lacking. However, while hypomagnesaemia, in the absence of diuretics, appears to rule out ADPKD and ARPKD, normomagnesaemia does not rule out RCAD at least in those aged <3 years. [ABSTRACT FROM AUTHOR]

Caroli's syndrome (CS; also known as Grumbach's disease) is characterized by non-obstructive intrahepatic bile ductal ectasia and dilatation, classified as mono- or multilobar, and it is associated with congenital hepatic fibrosis[1]. Signs of CD may not be visible during the early stages of pregnancy, and MRI may be helpful to detect liver biliary tree dilatation. [Extracted from the article]

The clinical effect of T118M variant of the PMP22 gene has been controversial. Several studies have suggested that it may be autosomal recessive, partial loss of function, or a benign variant. Here we report three cases in further support that the T118M variant of the PMP22 gene is a partial loss of function variant. These three unrelated cases were heterozygotes with the T118M variant of the PMP22 gene. All three cases presented with painful peripheral neuropathy and varying degrees of Charcot-Marie-Tooth exam features. Electrophysiological studies revealed polyneuropathy with axonal and demyelinating features in one case, but there were minimal electrophysiological changes in the other two cases. We propose that the T118M variant can cause painful peripheral neuropathy, which may be an underrecognized feature of this variant. [ABSTRACT FROM AUTHOR]

Combined and sequential liver-kidney transplantation (CLKT and SLKT) is a definitive treatment in children with end-stage organ failure. There are two major indications: - terminal insufficiency of both organs, or - need for transplanting new liver as a source of lacking enzyme or specific regulator of the immune system in a patient with renal failure. A third (uncommon) option is secondary end-stage renal failure in liver transplant recipients. These three clinical settings use distinct qualification algorithms. The most common indications include primary hyperoxaluria type 1 (PH1) and autosomal recessive polycystic kidney disease (ARPKD), followed by liver diseases associated with occasional kidney failure. Availability of anti-C5a antibody (eculizumab) has limited the validity of CLKT in genetic atypical hemolytic uremic syndrome (aHUS). The liver coming from the same donor as renal graft (in CLKT) is immunologically protective for the kidney and this provides long-term rejection-free follow-up. No such protection is observed in SLKT, when both organs come from different donors, except uncommon cases of living donation of both organs. Overall long-term outcome in CLKT in terms of graft survival is good and not different from isolated liver or kidney transplantation, however patient survival is inferior due to complexity of this procedure. [ABSTRACT FROM AUTHOR]

Background/Aims: Cardiovascular complications are the most common cause of death in individuals with autosomal dominant polycystic kidney disease (ADPKD), yet there is no substantial data concerning the clinical characteristics of acute myocardial infarction (AMI) in this population. This study thus aimed to investigate AMI in persons with ADPKD. Methods: A retrospective analysis of ADPKD patients admitted to our hospital over a 13 year period was conducted. Age and gender-matched control patients without ADPKD were also selected at a ratio of 1: 10. Results: A total of 52 ADPKD and 520 non-ADPKD patients were enrolled in the present study, with those in the former group exhibiting significantly poorer kidney function. The distribution of AMI types differed significantly between these two groups. The incidence of ST-segment elevation myocardial infarction (STEMI) was higher (75.0%) and the incidence of non-ST segment elevation myocardial infarction (NSTEMI) was lower (25.0%) in the ADPKD group. At the onset of AMI, sudden cardiac death (SCD) was more common in ADPKD patients (11.5% vs. 4.6%). In terms of risk factors, the occurrence of hypertension was greater in ADPKD patients (78.8% vs. 39.6%). With regard to subsequent management, ADPKD patients had a higher prevalence of triple-branch coronary lesions (21.1% vs. 11.2%), undergoing more coronary artery bypass grafting (CABG) (7.7% vs. 5.4%) and fewer percutaneous coronary interventions (PCI) (73.1% vs. 84.6%). Overall, ADPKD patients had higher rates of mortality (13.5% vs. 6.2%). Conclusion: ADPKD patients with AMI suffer from more severe conditions and difficult therapies, resulting in a poorer prognosis. [ABSTRACT FROM AUTHOR]

We present a family with two members affected by hyperekplexia and two unaffected members. All exons in the glycine receptor alpha 1 subunit gene (GLRA1) were sequenced in all four family members. Our index patient harbored a novel nonsense mutation (p.Trp314*; rs867618642) in the transmembrane domain three of the GLRA1 and a novel missense variant in the NH2-terminal part (p.Val67Met; rs142888296). After development of tolerance for the effective treatment with clobazam a drug holiday led to a sustained restoration of the treatment response. [ABSTRACT FROM AUTHOR]

Dubin-Johnson syndrome (DJS) is a rare, autosomal recessive disorder characterized by predominantly conjugated hyperbilirubinemia, caused by a mutation in the adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2) gene coding the multidrug resistance-associated protein 2 (MRP2) protein. ABCC2 mutations have been identified in patients with DJS worldwide; however, the mutation pattern of ABCC2 in China is not well studied. In the present study, the mutation pattern of the ABCC2 gene in Chinese patients with DJS was investigated. A total of 7 clinically confirmed patients with DJS were enrolled, and mutation analysis of the ABCC2 gene was performed by Sanger sequencing of genomic DNA extracted from whole blood. All 32 exons and the adjacent splice junction areas were sequenced. All cases were identified to harbor at least one non-synonymous variant in the ABCC2 gene, including three known mutations in 3 cases and three novel variants (p.G693R, p.G808V and p.E647X) in the other 4 cases, with the known p.R393W and the novel p.G693R and p.E647X variants identified in 2 of the 7 cases (28.6%), respectively. All the identified mutations were heterozygous, and 1 case presented with a compound heterozygous mutation, namely p.G693R/p.G808V, while the other cases carried only one single mutation. The loss of membrane expression of MRP2 caused by the novel nonsense variant, p.E647X, was confirmed by immunohistochemical analysis of liver biopsy. The present study provided the first report on the mutation patterns of the ABCC2 gene in Chinese patients with DJS, and the clinical association of these mutations with the syndrome. [ABSTRACT FROM AUTHOR]

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]

Purpose: to report phenotypic and genotypic features in a group of autosomal recessive retinitis pigmentosa (arRP) patients associated with EYS mutations. Methods: we retrospectively reviewed the clinical records and the molecular genetic data of arRP patients carrying mutations in the EYS gene. All the patients underwent a comprehensive opthalmological examination. Additional investigation included color fundus photography, fundus autofluorescence, Goldmann visual field, OCT scans and full-field standard electroretinography. Results: we studied 10 RP patients (20 eyes) characterized by mutations in the EYS gene. Thirteen different sequence variants in the EYS gene were identified. In total, nine mutations found in our series had not previously been reported in the literature. All patients in our series complained of typical RP symptoms at the onset of the disease, namely night blindness and progressive constriction of the visual field. Visual acuity ranged from light perception to 20/20. Relevant findings reported in our series are Interdigitation-zone (IZ band) involvement, present even in the milder phenotypes and an estimated prevalence of 6.2% of arRP associated with EYS mutations. Conclusions: we reported the mutation spectrum of a group of EYS-related RP patients including nine novel mutations and the associated clinical phenotypes. Our series is the largest group of EYS-related arRP patients in the Italian population. [ABSTRACT FROM AUTHOR]

Background: Autosomal recessive polycystic kidney disease (ARPKD) is genetically one of the least heterogeneous ciliopathies, resulting primarily from mutations of PKHD1. Nevertheless, 13-20% of patients diagnosed with ARPKD are found not to carry PKHD1 mutations by sequencing. Here, we assess whether PKHD1 copy number variations or second locus mutations explain these cases.Methods: Thirty-six unrelated patients with the clinical diagnosis of ARPKD were screened for PKHD1 point mutations and copy number variations. Patients without biallelic mutations were re-evaluated and screened for second locus mutations targeted by the phenotype, followed, if negative, by clinical exome sequencing.Results: Twenty-eight patients (78%) carried PKHD1 point mutations, three of whom on only one allele. Two of the three patients harbored in trans either a duplication of exons 33-35 or a large deletion involving exons 1-55. All eight patients without PKHD1 mutations (22%) harbored mutations in other genes (PKD1 (n = 2), HNF1B (n = 3), NPHP1, TMEM67, PKD1/TSC2). Perinatal respiratory failure, a kidney length > +4SD and early-onset hypertension increase the likelihood of PKHD1-associated ARPKD. A patient compound heterozygous for a second and a last exon truncating PKHD1 mutation (p.Gly4013Alafs*25) presented with a moderate phenotype, indicating that fibrocystin is partially functional in the absence of its C-terminal 62 amino acids.Conclusions: We found all ARPKD cases without PKHD1 point mutations to be phenocopies, and none to be explained by biallelic PKHD1 copy number variations. Screening for copy number variations is recommended in patients with a heterozygous point mutation. [ABSTRACT FROM AUTHOR]

Background: Autosomal dominant polycystic kidney disease (ADPKD) is an important cause of renal failure. Sparse recent data are available on clinical presentation ADPKD from India. Methods: We retrospectively studied the clinical presentation, imaging findings and laboratory abnormalities in 51 patients diagnosed to have ADPKD at our tertiary care teaching hospital at Tirupati, South India. Results: Their mean age at presentation was 49.1± 13.2 years; there were 32 (63%) males. Salient renal clinical manifestations at initial presentation included abdominal pain (47%); fever (35%), shortness of breath (33%); palpable mass per abdomen (25%); burning micturition (20%); haematuria (10%); and renal/ureteric caliculi (12%). Other manifestations were headache (21%); altered sensorium (12%); intracerebral bleed (8%) and chest pain (8%). Family history of ADPKD was present in 13 (26%) patients. On imaging studies kidneys were normal sized in 39%, enlarged in 59% and small sized in one patient; co-existent liver cysts were found in 12 patients. Hypertension (n = 20, 40%); chronic kidney disease (CKD) (n = 36, 71%) were evident at initial presentation. Other associated co-morbid conditions were type 2 diabetes mellitus (n = 6); Marfan's syndrome with mitral valve prolapsed and renal cell carcinoma (one patient each). Conclusions: In Tirupati, South India, ADPKD most commonly presented in fourth or fifth decade of life. Males were affected more frequently than females. Presence of CKD, hypertension at the time of inital diagnosis suggests that ADPKD is diagnosed late in the course of the disease. A high index of suspicion, specific diagnostic work-up including abdominal ultrasonography is required to diagnose ADPKD. [ABSTRACT FROM AUTHOR]

ABSTRACT: Aim: Type IV collagen nephropathies include Alport Syndrome and thin basement membrane nephropathy (TBMN), which are caused by mutations in COL4A3/A4/A5 genes. Recently, reports of patients with heterozygous mutations in COL4A3/A4 have been increasing. The clinical course of these patients has a wide variety, and they are diagnosed as TBMN, autosomal dominant Alport syndrome (ADAS), or familial focal segmental glomerular sclerosis. However, diagnosis, frequency and clinicopathological manifestation of them remains unclear. We tested COL4A3/A4/A5 genes in patients with hereditary nephritis that was difficult to diagnose clinicopathologically, and investigated who should undergo such testing. Methods: We performed immunostaining for α5 chain of type IV collagen [α5 (IV)] in 27 patients from 21 families who fitted the following criteria: (i) haematuria and proteinuria (± renal dysfunction); (ii) family history of haematuria, proteinuria, and/or renal dysfunction (autosomal dominant inheritance); (iii) no specific glomerulonephritis; and (iv) thinning, splitting, or lamellation of the glomerular basement membrane (GBM) on electron microscopy. Then we performed genetic testing in 19 patients from 16 families who showed normal α5 (IV) patterns. We conducted a retrospective analysis of their clinicopathological findings. Results: Among 16 families, 69% were detected heterozygous mutations in COL4A3/A4, suggesting the diagnosis of TBMN/ADAS. Twenty‐one percent of patients developed end stage renal disease. All patients showed thinning of GBM, which was accompanied by splitting or lamellation in seven patients. Conclusion: A considerable fraction of patients with hereditary nephritis that is difficult to diagnose clinicopathologically have TBMN/ADAS. It is important to recognize TBMN/ADAS and perform genetic testing in appropriate patients. [ABSTRACT FROM AUTHOR]

Polycystic kidney disease represented by autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) have a major impact of mortality in children. We conducted a study of a premature infant with an estimated gestation date of 32 weeks with a presumptive prenatal diagnosis of right polycystic kidney. A 28-year-old primigravida with pre-eclampsia was admitted at the gynecology unit of Clinical Emergency County Hospital of Craiova. The clinical examination revealed a large abdominal distention due probably to the right polycystic kidney, suspected on prenatal ultrasound and radiography. The preterm neonate undergone right nephrectomy 5 days after birth. Histopathology of the kidney was performed in the Pathology Department of the Emergency County Hospital of Craiova and in the Center for Microscopic Morphology and Immunology of U.M.F. of Craiova. Microscopy revealed dilated cysts lined by simple cuboidal or flattened epithelium, and islets of remnant kidney parenchyma separated by edematous stroma. Immunohistochemistry for CD34 revealed incomplete blood arcades which did not seem to be in contact with all the tubular elements of the parenchyma, when compared to a control age-matched kidney. The patient had a favorable postoperative evolution, she was clinically stable on discharge from the hospital with a follow-up strategy including genetic testing. [ABSTRACT FROM AUTHOR]

A novel autosomal recessive disorder characterized by pre‐ and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early mortality, hydrocephalus, and genital hypoplasia was observed in 4 children from 3 families of New Mexican Hispanic heritage. Three of the children died before 3 years of age from uremia and/or sepsis. Exome sequencing of the surviving individual identified a homozygous c.587T>C (p.Ile196Thr) mutation in ZPR1 Zinc Finger (ZPR1) that segregated appropriately in her family. In a second family, the identical variant was shown to be heterozygous in the affected individual's parents and not homozygous in any of her unaffected siblings. ZPR1 is a ubiquitously expressed, highly conserved protein postulated to transmit proliferative signals from the cell membrane to the nucleus. Structural modeling reveals that p.Ile196Thr disrupts the hydrophobic core of ZPR1. Patient fibroblast cells showed no detectable levels of ZPR1 and the cells showed a defect in cell cycle progression where a significant number of cells remained arrested in the G1 phase. We provide genetic and molecular evidence that a homozygous missense mutation in ZPR1 is associated with a rare and recognizable multisystem syndrome. [ABSTRACT FROM AUTHOR]

Background: Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease caused by a mutation in the AGXT gene, resulting in deficiency of the alanineglyoxylate:aminotransferase enzyme. It is characterized by accumulation of oxalate in the kidneys and other organs. Case Presentation: A Syrian woman with a history of nephrolithiasis and heterozygosity for factor V Leiden and prothrombin gene mutations presented with postpartum renal failure. She required initiation of renal replacement therapy at 14 weeks postpartum. Kidney biopsy showed severe acute and chronic crystalline deposition consistent with oxalate nephropathy. Genetic testing revealed a Gly170Arg mutation in the AGXT gene, confirming the diagnosis of PH1. Conclusions: The diagnosis of PH should be considered in patients with severe, recurrent calcium oxalate nephrolithiasis. Early treatment with pyridoxine reduces urinary oxalate excretion and can delay progression to end-stage renal disease (ESRD). After ESRD, intensive dialysis is needed to prevent systemic oxalate accumulation and deposition. Combined liver and kidney transplantation is curative. In our patient, we anticipate that liver transplantation will cure both the hyperoxaluria and the hypercoagulable state. [ABSTRACT FROM AUTHOR]

Background Cystic fibrosis (CF) is an autosomal recessive disease associated with chronic airway infections by Staphylococcus aureus as one of the earliest and most prevalent pathogens. We conducted a retrospective study to determine the S. aureus infection status of CF patients treated since 1994 at two certified CF-centres in Münster, Germany, to get insights into the dynamics of S. aureus airway infection and the clinical impact on lung function on a long-term perspective. Materials and methods We used data from our microbiological database collected between 1994 and 2016 for patients treated at two centres in Münster, Germany, respectively, to determine the infection status for S. aureus . Furthermore, the resistance to selected antibiotics was determined for all patients’ isolates and for 15 patients on a longitudinal basis. In addition, the prevalence of adaptive phenotypes such as small colony variants (SCVs) and mucoid S. aureus was assessed. Results For this study, 2867 patient years with respiratory specimens (mean of 9.3 years for every patient, range 1–22 years) were evaluated for 283 CF patients (median age of 7 years at the beginning of the observation period, range 0–57 years, 51% male). 18% of patients were rarely infected by S. aureus (≤24% of observation years), 20% of patients intermittently (25–49%) and 61% persistently (≥50% of observation period). Susceptibility testing for 12969 S. aureus isolates resulted in resistance to methicillin in 9%, trimethoprim/sulfamethoxazole in 10%, levofloxacin in 14%, gentamicin in 20%, erythromycin and/or clindamycin in 30% and penicillin in 80% of all isolates. S. aureus isolates of 15 patients revealed dynamics of resistance with increase, decrease and loss of resistant isolates to the analysed antibiotics during the study period. SCVs were isolated at least once from 42% (n = 118) of patients and mucoid isolates from 2% (n = 7) of patients. In the last study year, 89 patients were infected by S. aureus only, 44 patients by S. aureus and Pseudomonas aeruginosa and 18 by P. aeruginosa only. Patients infected by S. aureus only were younger and had better lung function compared to the other two groups. Conclusions We determined a high percentage of patients with persistent S. aureus infection. During persistence, mostly fluctuation of resistance against various antibiotics was observed in the isolates indicating acquisition and loss of resistance genes by S. aureus . The prevalence of adaptive phenotypes during long-term persistence was high for SCVs (42% of patients), but low for mucoid isolates (2% of patients), which might be underestimated for mucoid phenotypes due to the retrospective study design and the difficulty to detect mucoid isolates in primary cultures. While patients with S. aureus only had better lung function and were younger, no difference was found between the group of P. aeruginosa and S. aureus co-infection and P. aeruginosa only with previous S. aureus infection. [ABSTRACT FROM AUTHOR]

The article reports on the management of abdominoperineal excision of the rectum in a patient with glanmann thrombasthenia (GT). Topics discussed include GT as a rare inherited autosomal recessive disorder of platelet aggregation due to aberrant or absent glycoprotein IIb/IIIa on the platelet surface with impaired binding of fibrinogen, and hypersensitivity reaction to platelet transfusions.

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/Aims: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder with mutations in PKD1 or PKD2. This study aimed to identify novel PKD1 and PKD2 mutations in Chinese patients with ADPKD. Methods: Mutational analyses of both PKD genes were performed in 120 Chinese families with inherited ADPKD using long-range PCR and targeted next-generation sequencing approaches. Sanger sequencing was performed to check the positive mutations, while multiplex ligation-dependent probe amplification was adopted to examine those without mutations for the presence of large deletions. Results: A total of 93 mutations in PKD1 and PKD2 were identified in 98 Chinese families with ADPKD inheritance and the detection rate was 81.7% (98/120). The mutation rates of PKD1 and PKD2 were 91.4% (85/93) and 8.6% (85/93), respectively. Among the 93 mutations, 59.1% (55/93) were reported for the first time. A total of 65 mutations (26 nonsense, 33 frameshift, 2 large deletion, and 4 typical splicing mutations) were identified as definite pathogenic mutations. The remaining 28 mutations (21 missense, 3 in-frame deletion, and 4 atypical splicing mutations) were determined as probable pathogenic mutations. In addition, 9 de novo mutations were found by pedigree analysis. Correlation analysis between genotype and phenotype revealed that patients with PKD1 mutations or truncating mutations exhibited the most severe clinical outcome. Conclusion: The newly identified sites for known mutations will facilitate the early diagnosis and prediction of prognosis in patients with ADPKD, and provide fundamental genetic information for clinical intervention to prevent the inheritance of this disease in affected families. [ABSTRACT FROM AUTHOR]

Aniridia is a rare congenital ocular malformation that follows an autosomal dominant mode of inheritance. Most patients carry pathogenic point mutations in the paired box 6 gene (PAX6), but some carry deletions involving the 11p13 region, encompassing partly or completely PAX6 or the region downstream. We identified a novel deletion, ∼564 kb in size located about 46.5 kb downstream of PAX6 in a family with bilateral aniridia and foveal hypoplasia using array-CGH and multiplex ligation-dependent probe amplification. We also review all of the reported deletions downstream of PAX6 in patients with aniridia and/or other congenital malformations and define the overlapping region that leads to aniridia when deleted. [ABSTRACT FROM AUTHOR]

Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder but even rarer in Africans and it is one of the causes of nephropathies in childhood. Although isolated cases of adult PKD have been reported in Nigerians; to the best of our knowledge, this case is the first to be reported in the paediatric age group in Nigeria. A case of autosomal recessive polycystic kidney disease presenting with severe perinatal asphyxia and severe respiratory distressis here by presented. Fetal ultrasonography during the pregnancy missed the diagnosis. The difficulty in making diagnosis and management is discussed. Autopsy helped to unravel the diagnosis in this case report. [ABSTRACT FROM AUTHOR]

Hypomyelinating leukodystrophies (HLDs) affect the white matter of the central nervous system and manifest as neurological disorders. They are genetically heterogeneous. Very recently, biallelic variants in NKX6‐2 have been suggested to cause a novel form of autosomal recessive HLD. Using whole‐exome or whole‐genome sequencing, we identified the previously reported c.196delC and c.487C>G variants in NKX6‐2 in 3 and 2 unrelated index cases, respectively; the novel c.608G>A variant was identified in a sixth patient. All variants were homozygous in affected family members only. Our patients share a primary diagnosis of psychomotor delay, and they show spastic quadriparesis, nystagmus and hypotonia. Seizures and dysmorphic features (observed in 2 families each) represent an addition to the phenotype, while developmental regression (observed in 3 families) appears to be a notable and previously underestimated clinical feature. Our findings extend the clinical and mutational spectra associated with this novel form of HLD. Comparative analysis of our 10 patients and the 15 reported previously did, however, not reveal clear evidence for a genotype‐phenotype correlation. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa (RP) is a group of hereditary, degenerative retinal disorders characterized by progressive retinal dysfunction, outer retina cell loss, and retinal tissue atrophy. It eventually leads to tunnel vision and legal or total blindness. Here, we aimed to reveal the causal gene and mutation contributing to the development of autosomal recessive RP (arRP) in a consanguineous family. A novel homozygous mutation, c.4845delT (p.K1616Rfs*46), in the ATP-binding cassette subfamily A member 4 gene (ABCA4) was identified. It may reduce ABCA4 protein activity, leading to progressive degeneration of both rod and cone photoreceptors. The study extends the arRP genotypic spectrum and con- firms a genotype--phenotype relationship. The present study may also disclose some new clues for RP genetic causes and pathogenesis, as well as clinical and genetic diagnosis. The research findingsmay contribute to improvement in clinical care, therapy, genetic screening, and counseling. [ABSTRACT FROM AUTHOR]

Niemann-Pick-disease type C1 (NPC1) is an autosomal-recessive cholesterol-storage disorder. Besides other symptoms, NPC1 patients develop liver dysfunction and hepatosplenomegaly. The mechanisms of hepatomegaly and alterations of lipid metabolism-related genes in NPC1 disease are still poorly understood. Here, we used an NPC1 mouse model to study an additive hepatoprotective effect of a combination of 2-hydroxypropyl-β-cyclodextrin (HPβCD), miglustat and allopregnanolone (combination therapy) with the previously established monotherapy using HPβCD. We examined transgene effects as well as treatment effects on liver morphology and hepatic lipid metabolism, focusing on hepatic cholesterol transporter genes. Livers of Npc1-/- mice showed hepatic cholesterol sequestration with consecutive liver injury, an increase of lipogenetic gene expression, e.g., HMG-CoA, a decrease of lipolytic gene expression, e.g., ppara and acox1, and a decrease of lipid transporter gene expression, e.g., acat1, abca1 and fatp2. Both, combination therapy and monotherapy, led to a reduction of hepatic lipids and an amelioration of NPC1 liver disease symptoms. Monotherapy effects were related to ppara- and acox1-associated lipolysis/β-oxidation and to fatp2-induced fatty acid transport, whereas the combination therapy additionally increased the cholesterol transport via abca1 and apoE. However, HPβCD monotherapy additionally increased cholesterol synthesis as indicated by a marked increase of the HMG-CoA and srebp-2 mRNA expression, probably as a result of increased hepatocellular proliferation. [ABSTRACT FROM AUTHOR]

Polycystic kidney disease (PKD) encompasses a group of genetic disorders that are common causes of renal failure. The two classic forms of PKD are autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD). Despite their clinical differences, ARPKD and ADPKD share many similarities. Altered intracellular Ca2+ and increased cyclic adenosine monophosphate (cAMP) concentrations have repetitively been described as central anomalies that may alter signaling pathways leading to cyst formation. The vasopressin V2 receptor (V2R) antagonist tolvaptan lowers cAMP in cystic tissues and slows renal cystic progression and kidney function decline when given over 3 years in adult ADPKD patients. Tolvaptan is currently approved for the treatment of rapidly progressive disease in adult ADPKD patients. On the occasion of the recent initiation of a clinical trial with tolvaptan in pediatric ADPKD patients, we aim to describe the most important aspects in the literature regarding the AVP-cAMP axis and the clinical use of tolvaptan in PKD. [ABSTRACT FROM AUTHOR]

Objective(s): Targeted next-generation sequencing (NGS) provides a consequential opportunity to elucidate genetic factors in known diseases, particularly in profoundly heterogeneous disorders such as non-syndromic hearing loss (NSHL). Hearing impairments could be classified into syndromic and nonsyndromic types. This study intended to assess the significance of mutations in these genes to the autosomal recessive/dominant non-syndromic genetic load among Iranian families. Materials and Methods: Two families were involved in this research and two patients were examined by targeted next-generation sequencing. Here we report two novel mutations in the MYO7A and EYA1 genes in two patients detected by targeted NGS. They were confirmed by Sanger sequencing and quantitative real-time PCR techniques. Results: In this investigation, we identified a novel mutation in MYO7A, c.3751G>C, p.A1251P, along with another previously identified mutation (c.1708C>T) in one of the cases. This mutation is located in the MYTH4 protein domain which is a pivotal domain for the myosin function. Another finding in this research was a novel de-novo deletion which deletes the entire EYA1 coding region (EX1-18 DEL). Mutations in EYA1 gene have been found in branchiootorenal (BOR) syndrome. Interestingly the patient with EYA1 deletion did not show any other additional clinical implications apart from HL. This finding might argue for the sole involvement of EYA1 function in the mechanism of hearing. Conclusion: This investigation exhibited that the novel mutations in MYO7A, c.3751G>C, p.A1251P, and EYA1, EX1-18 DEL, were associated with NSHL. Our research increased the mutation spectrum of hearing loss in the Iranian population. [ABSTRACT FROM AUTHOR]

Background: Liddle syndrome is an autosomal dominant form of monogenic hypertension. Phenotypic variability makes it difficult to identify patients with Liddle syndrome, resulting in misdiagnosis and severe complications at early age.Objectives: To identify mutation inSCNN1BandSCNN1Ggenes in an adolescent with suspicious Liddle syndrome and his family members and to explore the screening target subjects of Liddle syndrome.Methods: Genetic analysis of the C-terminus ofSCNN1BandSCNN1Ggenes was conducted in an adolescent, with treatment-resistant hypertension and hypokalemia, who was suspected of having Liddle syndrome, and his family members. A Medline research of the reported cases with Liddle syndrome was also performed.Results: A recurrentSCNN1Bmutation, c.1853C>A (p.P618H), was detected in the 19-year-old male patient, and family screening identified five additional members who were heterozygous for the mutation. The diagnosis of Liddle syndrome was made in all affected individuals. Despite the phenotypic variability, a systematic review of 54 reported index cases revealed the early-onset hypertension, aged no more than 30 years, as a common feature.Conclusions: Genetic screening for Liddle syndrome should be considered in hypertensive subjects with early penetrance, maybe no more than 30 years, after exclusion of common secondary causes of hypertension. [ABSTRACT FROM AUTHOR]

Triple A syndrome (TAS) or Allgrove syndrome (OMIM #231550) is a rare autosomal recessive disorder characterised by adrenocorticotropic hormone-resistant adrenal insufficiency, alacrima, achalasia, and neurological and dermatological abnormalities. Mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN have been reported in these patients. Between 2006 and 2017, we evaluated six patients with a clinical diagnosis of TAS, based on the presence of at least two symptoms, usually adrenal insufficiency and alacrima. In all cases, genetic analysis revealed homozygous mutations in the AAAS gene. One novel mutation was detected: a homozygous 10-bp deletion (c.1264_1273del, p.Q422NfsX126) in exon 14 of the AAAS gene that caused a frameshift that introduced an aberrant stop codon after 126 amino acids. This genetic variant is likely to be pathogenic because it caused a significant change in protein structure. A precise genotype-phenotype correlation was impossible to establish.Conclusions: Based on our experience, we recommend that molecular analysis should be performed in the presence of alacrima and at least one more symptom of TAS. Our cases share many clinical features of TAS and underline the variability in this syndrome, as well as the need for thorough investigation following a multidisciplinary approach. What is known: • Triple A syndrome is characterised by achalasia, alacrima, adrenal insufficiency, neurological impairment, and dermatological abnormalities. • A precise genotype-phenotype correlation has proved impossible to establish. What is new: • These cases add to a large number of similar case reports with limited novel information. • The newly identified AAAS gene mutation was reported. [ABSTRACT FROM AUTHOR]

Abstract: We present a case of a 2‐year‐old child who underwent a combined en bloc liver and pancreas transplant following complications of WRS. WRS is characterized clinically through infantile insulin‐dependent diabetes mellitus, neutropenia, recurrent infections, propensity for liver failure following viral infections, bone dysplasia, and developmental delay. Usually, death occurs from fulminant liver and concomitant kidney failure. Few cases with WRS are reported in the literature, mostly from consanguineous parents. To the best of our knowledge, combined en bloc liver and pancreas transplant has not been performed in small children. [ABSTRACT FROM AUTHOR]

Introduction: Liver-kidney transplantation is a rare procedure in children, with just ten to 30 cases performed annually worldwide. The main indications are autosomal recessive polycystic liver-kidney disease and primary hyperoxaluria. This study aimed to report outcomes of liver-kidney transplantation in a cohort of pediatric patients. Methods: We retrospectively analyzed all pediatric liver-kidney transplantations performed in our center between September 2000 and August 2015. Patient data were obtained by reviewing inpatient and outpatient medical records and our transplant database. Results: A total of 14 liver-kidney transplants were performed during the study period, with a median patient age and weight at transplant of 144.4 months (131.0-147.7) and 27.3 kg (12.0-45.1), respectively. The indications for liver-kidney transplants were autosomal recessive polycystic liver-kidney disease (8/14), primary hyperoxaluria −1 (5/14), and idiopathic portal hypertension with end-stage renal disease (1/14). Median time on waiting list was 8.5 months (5.7-17.3). All but two liver-kidney transplants were performed simultaneously. Patients with primary hyperoxaluria-1 tended to present a delayed recovery of renal function compared with patients transplanted for other indications (62.5 vs 6.5 days, respectively, P 0.076). Patients with liver-kidney transplants tended to present a lower risk of acute kidney rejection than patients transplanted with an isolated kidney transplant (7.2% vs 32.7%, respectively; P < 0.07). Patient and graft survival at 1, 3, and 5 years were 100%, 91.7%, 91.7%, and 91.7%, 83.3%, 83.3%, respectively. No other grafts were lost. Conclusion: Long-term results of liver-kidney transplants in children are encouraging, being comparable with those obtained in isolated liver transplantation. [ABSTRACT FROM AUTHOR]

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder characterized by progressive cyst formation and expansion in the kidneys, which culminates in end-stage renal disease. Aortic dissection is a rare vascular complication of ADPKD and related literature is currently limited. Case presentation: In this report, we described a patient with asymptomatic Stanford B aortic dissection. Further investigation revealed a positive family history of ADPKD and normal renal function. Whole exome sequencing identified a stop-gain mutation c.1774C > T, p.Arg592Ter in the PKD2 gene that segregated in the family. To our knowledge, this is the first report of ADPKD complicated with aortic dissection caused by PKD2 mutation. Conclusions: The case illustrates the importance of aorta imaging and molecular diagnosis in ADPKD patients in order to achieve early recognition of the deadly vascular complication. [ABSTRACT FROM AUTHOR]

Congenital or neonatal cardiomyopathies are commonly associated with a poor prognosis and have multiple etiologies. In two siblings, a male and female, we identified an undescribed type of lethal congenital restrictive cardiomyopathy affecting the right ventricle. We hypothesized a novel autosomal recessive condition. To identify the cause, we performed genetic, in vitro and in vivo studies. Genome-wide SNP typing and parametric linkage analysis was done in a recessive model to identify candidate regions. Exome sequencing analysis was done in unaffected and affected siblings. In the linkage regions, we selected candidate genes that harbor two rare variants with predicted functional effects in the patients and for which the unaffected sibling is either heterozygous or homozygous reference. We identified two compound heterozygous variants in KIF20A; a maternal missense variant (c.544C>T: p.R182W) and a paternal frameshift mutation (c.1905delT: p.S635Tfs*15). Functional studies confirmed that the R182W mutation creates an ATPase defective form of KIF20A which is not able to support efficient transport of Aurora B as part of the chromosomal passenger complex. Due to this, Aurora B remains trapped on chromatin in dividing cells and fails to translocate to the spindle midzone during cytokinesis. Translational blocking of KIF20A in a zebrafish model resulted in a cardiomyopathy phenotype. We identified a novel autosomal recessive congenital restrictive cardiomyopathy, caused by a near complete loss-of-function of KIF20A. This finding further illustrates the relationship of cytokinesis and congenital cardiomyopathy. [ABSTRACT FROM AUTHOR]

Background: Non-ketotic hyperglycinemia (NKH) is a rare, devastating autosomal recessive disorder of glycine metabolism with a very poor prognosis. Currently, few studies have reported genetic profiling of Chinese NKH patients. This study aimed to identify the genetic mutations in a Chinese family with NKH. Methods: A Chinese family of Han ethnicity, with three siblings with NKH was studied. Sanger sequencing and multiplex ligation-dependent probe amplification combined with SYBR green real-time quantitative PCR was used to identify potential mutations in the GLDC, AMT and GCSH genes. The potential pathogenicity of the identified missense mutation was analyzed using SIFT, PolyPhen-2, PROVEAN and MutationTaster software. Results: All patients exhibited severe and progressive clinical symptoms, including lethargy, hypotonia and seizures, and had greatly elevated glycine levels in their plasma and CSF. Molecular genetic analysis identified compound heterozygous variants in the GLDC gene in these three siblings, including a novel missense variant c.2680A > G (p.Thr894Ala) in exon 23 and a heterozygous deletion of exon 3, which were inherited respectively from their parents. In silico analysis, using several different types of bioinformatic software, predicted that the novel variant c.2680A > G in the GLDC gene was pathogenic. Moreover, the deletion of exon 3 was identified for the first time in a Chinese population. Conclusions: A novel missense variant and a previously reported deletion in GLDC gene were identified. The two variants of GLDC gene identified probably underlie the pathogenesis of non-ketotic hyperglycinemia in this family, and also enrich the mutational spectrum of GLDC gene. [ABSTRACT FROM AUTHOR]

Abstract: Background: Gout is a clinical syndrome that occurs as an inflammatory response to increased concentration of uric acid and monosodium urate crystals. Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease with autosomal recessive inheritance. The Mediterranean fever (MEFV) gene is responsible for FMF and encodes pyrin that suppresses the inflammatory response. Most of the FMF‐related mutations have been identified in exon 2 (e.g., E148Q and R202Q) and exon 10 (M680I, M694V, M694I and V726A) of the MEFV gene, and each missense mutation is known to increase production of interleukin‐1, a proinflammatory cytokine. Our aim was to investigate effects of MEFV variant alleles on the manifestations of gout. Methods: Seventy‐one patients diagnosed with gout (age: 61.73 ± 11.73 years, F/M: 14/57) and 50 healthy subjects (age: 61.48 ± 11.97, F/M: 10/40) as controls were included in this study. Results: MEFV variant alleles were found in 24 (33.8%) of the gout patients and in 13 (26%) of the control subjects; the difference was not statistically significant. In the gout patients with a MEFV variant allele, the interval between the first two attacks was shorter (P = 0.014), and the platelet count was higher (P = 0.026), compared to the patients without a variant allele. In addition, the patients with a MEFV variant allele showed the higher incidence of tophus (8.5% vs. 1.4%) (P = 0.005) and the higher number of attacks per year (P = 0.001). Conclusion: We propose that a variant allele of the MEFV gene may be responsible for the severity of gout. [ABSTRACT FROM AUTHOR]