Publications by authors named "Zoran Gucev"

94 Publications

Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux.

J Am Soc Nephrol 2021 Feb 17. Epub 2021 Feb 17.

Division of Nephrology, Department of Medicine, Columbia University, New York, New York

Background: Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood.

Methods: A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. A GWAS was performed in 1395 patients and 5366 controls, of European ancestry.

Results: Altogether, 3% of VUR patients harbored an undiagnosed rare CNV disorder, such as the 1q21.1, 16p11.2, 22q11.21, and triple X syndromes ((OR, 3.12; 95% CI, 2.10 to 4.54; =6.35×10) The GWAS identified three study-wide significant and five suggestive loci with large effects (ORs, 1.41-6.9), containing canonical developmental genes expressed in the developing urinary tract ( and ). In particular, 3.3% of VUR patients were homozygous for an intronic variant in (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; =1.86×10). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis.

Conclusions: These data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of patients with VUR harbored a rare CNV or a common variant genotype conferring an OR >3. Identification of these genetic risk factors has multiple implications for clinical care and for analysis of outcomes in VUR.
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http://dx.doi.org/10.1681/ASN.2020050681DOI Listing
February 2021

Rare heterozygous GDF6 variants in patients with renal anomalies.

Eur J Hum Genet 2020 12 31;28(12):1681-1693. Epub 2020 Jul 31.

Department of Human Genetics, Hannover Medical School, 30625, Hannover, Germany.

Although over 50 genes are known to cause renal malformation if mutated, the underlying genetic basis, most easily identified in syndromic cases, remains unsolved in most patients. In search of novel causative genes, whole-exome sequencing in a patient with renal, i.e., crossed fused renal ectopia, and extrarenal, i.e., skeletal, eye, and ear, malformations yielded a rare heterozygous variant in the GDF6 gene encoding growth differentiation factor 6, a member of the BMP family of ligands. Previously, GDF6 variants were reported to cause pleiotropic defects including skeletal, e.g., vertebral, carpal, tarsal fusions, and ocular, e.g., microphthalmia and coloboma, phenotypes. To assess the role of GDF6 in the pathogenesis of renal malformation, we performed targeted sequencing in 193 further patients identifying rare GDF6 variants in two cases with kidney hypodysplasia and extrarenal manifestations. During development, gdf6 was expressed in the pronephric tubule of Xenopus laevis, and Gdf6 expression was observed in the ureteric tree of the murine kidney by RNA in situ hybridization. CRISPR/Cas9-derived knockout of Gdf6 attenuated migration of murine IMCD3 cells, an effect rescued by expression of wild-type but not mutant GDF6, indicating affected variant function regarding a fundamental developmental process. Knockdown of gdf6 in Xenopus laevis resulted in impaired pronephros development. Altogether, we identified rare heterozygous GDF6 variants in 1.6% of all renal anomaly patients and 5.4% of renal anomaly patients additionally manifesting skeletal, ocular, or auricular abnormalities, adding renal hypodysplasia and fusion to the phenotype spectrum of GDF6 variant carriers and suggesting an involvement of GDF6 in nephrogenesis.
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http://dx.doi.org/10.1038/s41431-020-0678-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784874PMC
December 2020

Exome Sequencing and Identification of Phenocopies in Patients With Clinically Presumed Hereditary Nephropathies.

Am J Kidney Dis 2020 10 28;76(4):460-470. Epub 2020 Apr 28.

Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany. Electronic address:

Rationale & Objective: Hereditary nephropathies are clinically and genetically heterogeneous disorders. For some patients, the clinical phenotype corresponds to a specific hereditary disease but genetic testing reveals that the expected genotype is not present (phenocopy). The aim of this study was to evaluate the spectrum and frequency of phenocopies identified by using exome sequencing in a cohort of patients who were clinically suspected to have hereditary kidney disorders.

Study Design: Cross-sectional cohort study.

Setting & Participants: 174 unrelated patients were recruited for exome sequencing and categorized into 7 disease groups according to their clinical presentation. They included autosomal dominant tubulointerstitial kidney disease, Alport syndrome, congenital anomalies of the kidney and urinary tract, ciliopathy, focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome, VACTERL association, and "other."

Results: A genetic diagnosis (either likely pathogenic or pathogenic variant according to the guidelines of the American College of Medical Genetics) was established using exome sequencing in 52 of 174 (30%) cases. A phenocopy was identified for 10 of the 52 exome sequencing-solved cases (19%), representing 6% of the total cohort. The most frequent phenocopies (n=5) were associated with genetic Alport syndrome presenting clinically as focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome. Strictly targeted gene panels (<25 kilobases) did not identify any of the phenocopy cases.

Limitations: The spectrum of described phenocopies is small. Selection bias may have altered the diagnostic yield within disease groups in our study population. The study cohort was predominantly of non-Finnish European descent, limiting generalizability. Certain hereditary kidney diseases cannot be diagnosed by using exome sequencing (eg, MUC1-autosomal dominant tubulointerstitial kidney disease).

Conclusions: Phenocopies led to the recategorization of disease and altered clinical management. This study highlights that exome sequencing can detect otherwise occult genetic heterogeneity of kidney diseases.
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http://dx.doi.org/10.1053/j.ajkd.2019.12.008DOI Listing
October 2020

A Comprehensive Cohort Analysis Comparing Growth and GH Therapy Response in IGF1R Mutation Carriers and SGA Children.

J Clin Endocrinol Metab 2020 04;105(4)

Center for Pediatric Research Leipzig, University Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany.

Context: IGF1 receptor mutations (IGF1RM) are rare; however, patients exhibit pronounced growth retardation without catch-up. Although several case reports exist, a comprehensive statistical analysis investigating growth profile and benefit of recombinant human growth hormone (rhGH) treatment is still missing.

Objective And Methods: Here, we compared IGF1RM carriers (n = 23) retrospectively regarding birth parameters, growth response to rhGH therapy, near final height, and glucose/insulin homeostasis to treated children born small for gestational age (SGA) (n = 34). Additionally, health profiles of adult IGF1RM carriers were surveyed by a questionnaire.

Results: IGF1RM carriers were significantly smaller at rhGH initiation and had a diminished first-year response compared to SGA children (Δ height standard deviation score: 0.29 vs. 0.65), resulting in a lower growth response under therapy. Interestingly, the number of poor therapy responders was three times higher for IGF1RM carriers than for SGA patients (53 % vs. 17 %). However, most IGF1RM good responders showed catch-up growth to the levels of SGA patients. Moreover, we observed no differences in homeostasis model assessment of insulin resistance before treatment, but during treatment insulin resistance was significantly increased in IGF1RM carriers compared to SGA children. Analyses in adult mutation carriers indicated no increased occurrence of comorbidities later in life compared to SGA controls.

Conclusion: In summary, IGF1RM carriers showed a more pronounced growth retardation and lower response to rhGH therapy compared to non-mutation carriers, with high individual variability. Therefore, a critical reevaluation of success should be performed periodically. In adulthood, we could not observe a significant influence of IGF1RM on metabolism and health of carriers.
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http://dx.doi.org/10.1210/clinem/dgz165DOI Listing
April 2020

Severe digital malformations in a rare variant of fibrodysplasia ossificans progressiva.

Am J Med Genet A 2019 07 22;179(7):1310-1314. Epub 2019 Apr 22.

Department of Orthopaedic Surgery, Center for Research in FOP & Related Disorders, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania.

A 16-year-old girl with a history of nontraumatic swelling of both forearms, osteochondromas of the knees, heterotopic ossification of the neck and back, severe malformations of all digits with hypoplastic or absent nails, alopecia partialis of the scalp, and moderate cognitive impairment was seen for diagnostic evaluation. Whole exome sequencing identified an activating mutation of ACVR1 (c.983G > A; p.Gly328Glu) which confirmed a suspected FOP variant. The delayed diagnosis of an FOP variant in this patient could have been avoided if the significance of severe digital malformations had been recognized, especially in the setting of progressive heterotopic ossification.
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http://dx.doi.org/10.1002/ajmg.a.61153DOI Listing
July 2019

Tissue-specific mosaicism in a patient with Rubinstein-Taybi syndrome and CREBBP exon 1 duplication.

Clin Dysmorphol 2019 Jul;28(3):142-144

Institute of Human Genetics, University Medical Centre of the Johannes Gutenberg University, Mainz, Mainz, Germany.

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http://dx.doi.org/10.1097/MCD.0000000000000268DOI Listing
July 2019

A 4-Year-Old Boy with Beckwith Wiedemann Syndrome (BWS).

Pril (Makedon Akad Nauk Umet Odd Med Nauki) 2018 Dec;39(2-3):131-135

Center for Human Genetics, Bioscientia Institute for Medical Diagnostics Ingelheim, Germany.

Objectives: Molecular characterization of a patient with BWS.

Clinical Presentation And Intervention: A 4-year-old boy with overgrowth (weight above 99th and height at 99th percentile) had longitudinal hemihypertrophy of the tongue and left cheek. In addition, there was a difference of one centimeter in the circumference of the left and right leg. Molecular genetic analysis revealed hypomethylation of KvDRM1 (LIT1) in the imprinting control region-2 (ICR2) on chromosome 11p15.5 and a normal methylation pattern of the H19-differentially methylated region (H19-DMR) in the ICR1. The estimated tumor risk was 1-5%.

Conclusion: This patient with clinical characteristics of BWS has an imprinting defect associated with a low risk of embryonal tumors.
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http://dx.doi.org/10.2478/prilozi-2018-0052DOI Listing
December 2018

Author Correction: The copy number variation landscape of congenital anomalies of the kidney and urinary tract.

Nat Genet 2019 04;51(4):764

Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA.

In the version of this article initially published, affiliation 38 incorrectly read "ICNU-Nephrology and Urology Department, Barcelona, Spain"; "Renal Division, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain" is the correct affiliation. The error has been corrected in the HTML and PDF versions of the article.
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http://dx.doi.org/10.1038/s41588-019-0376-0DOI Listing
April 2019

Treatment and long-term outcome in primary distal renal tubular acidosis.

Nephrol Dial Transplant 2019 06;34(6):981-991

Department of Paediatric Nephrology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK.

Background: Primary distal renal tubular acidosis (dRTA) is a rare disorder, and we aimed to gather data on treatment and long-term outcome.

Methods: We contacted paediatric and adult nephrologists through European professional organizations. Responding clinicians entered demographic, biochemical, genetic and clinical data in an online form.

Results: Adequate data were collected on 340 patients (29 countries, female 52%). Mutation testing had been performed on 206 patients (61%); pathogenic mutations were identified in 170 patients (83%). The median (range) presentation age was 0.5 (0-54) years and age at last follow-up was 11.0 (0-70.0) years. Adult height was slightly below average with a mean (SD score) of -0.57 (±1.16). There was an increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (35%) and adults (82%). Nephrocalcinosis was reported in 88%. Nephrolithiasis was more common with SLC4A1 mutations (42% versus 21%). Thirty-six percent had hearing loss, particularly in ATP6V1B1 (88%). The median (interquartile range) prescribed dose of alkali (mEq/kg/day) was 1.9 (1.2-3.3). Adequate metabolic control (normal plasma bicarbonate and normocalciuria) was achieved in 158 patients (51%), more commonly in countries with higher gross domestic product (67% versus 23%), and was associated with higher height and estimated glomerular filtration rate.

Conclusion: Long-term follow-up from this large dRTA cohort shows an overall favourable outcome with normal adult height for most and no patient with CKD Stage 5. However, 82% of adult patients have CKD Stages 2-4. Importance of adequate metabolic control was highlighted by better growth and renal function but was achieved in only half of patients.
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http://dx.doi.org/10.1093/ndt/gfy409DOI Listing
June 2019

Heterotopic ossifications and Charcot joints: Congenital insensitivity to pain with anhidrosis (CIPA) and a novel NTRK1 gene mutation.

Eur J Med Genet 2020 Jan 21;63(1):103613. Epub 2019 Jan 21.

Institute of Human Genetics, Medical Center of the Johannes Gutenberg University Mainz, University of Mainz, Germany.

Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN-IV), is a rare and severe autosomal recessive disorder. We report on an adult female patient whose clinical findings during childhood were not recognized as CIPA. There was neither complete anhidrosis nor a recognizable sensitivity to heat. Tumorlike swellings of many joints and skeletal signs of Charcot neuropathy developed in adolescence which, together with a history of self-mutilation, led to a clinical suspicion of CIPA confirmed by identification of a novel homozygous variant c.1795G > T in the NTRK1 gene in blood lymphocytes. Both parents were heterozygous for the mutation. The variant predicts a premature stop codon (p.Gly599Ter) and thus represents a pathogenic variant; the first reported in the Southeastern European population.
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http://dx.doi.org/10.1016/j.ejmg.2019.01.003DOI Listing
January 2020

The copy number variation landscape of congenital anomalies of the kidney and urinary tract.

Nat Genet 2019 01 21;51(1):117-127. Epub 2018 Dec 21.

Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.
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http://dx.doi.org/10.1038/s41588-018-0281-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668343PMC
January 2019

Gene Alterations in Children Born Small for Gestitional Age (SGA).

Open Access Maced J Med Sci 2018 Nov 10;6(11):2040-2044. Epub 2018 Nov 10.

University of Leipzig, Leipzig, Germany.

Background: Small for gestational age (SGA)-born children are a heterogeneous group with few genetic causes reported. Genetic alterations in the IGF1 receptor (IGF1R) are found in some SGA children.

Aim: To investigate whether alterations in gene are present in SGA born children.

Patients And Methods: We analysed 64 children born SGA who stayed short (mean -3.25 ± 0.9 SDS) within the first 4 years of age, and 36 SGA children who caught up growth (0.20 ± 1.1 SDS). PCR products of all coding IGF1R exons were screened by dHPLC followed by direct sequencing of conspicuous fragments to identify small nucleotide variants. The presence of IGF1R gene copy number alterations was determined by Multiplex Ligation-dependent Probe Amplification (MLPA).

Results: The cohort of short SGA born children revealed a heterozygous, synonymous variant c.3453C > T in one patient and a novel heterozygous 3 bp in-frame deletion (c.3234_3236delCAT) resulting in one amino acid deletion (p.Ile1078del) in another patient. The first patient had normal serum levels of IGF1. The second patient had unusually low IGF1 serum concentrations (-1.57 SD), which contrasts previously published data where IGF1 levels rarely are found below the age-adjusted mean.

Conclusions: gene alterations were present in 2 of 64 short SGA children. The patients did not have any dysmorphic features or developmental delay. It is remarkable that one of them had significantly decreased serum concentrations of IGF1. Growth response to GH treatment in one of the patients was favourable, while the second one discontinued the treatment, but with catch-up growth.
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http://dx.doi.org/10.3889/oamjms.2018.416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290431PMC
November 2018

Homeostasis Model Assessment - Insulin Resistance and Sensitivity (HOMA-IR and IS) Index in Overweight Children Born Small for Gestational Age (SGA).

Pril (Makedon Akad Nauk Umet Odd Med Nauki) 2018 Jul;39(1):83-89

Macedonian Academy of Siences and Arts, Skopje, Republic of Macedonia.

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http://dx.doi.org/10.2478/prilozi-2018-0027DOI Listing
July 2018

Low Molecular Weight Proteinuria in Children with Distal Renal Tubular Acidosis.

Pril (Makedon Akad Nauk Umet Odd Med Nauki) 2018 Jul;39(1):91-95

University Children's Hospital, Medical School Skopje, Republic of Macedonia.

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http://dx.doi.org/10.2478/prilozi-2018-0028DOI Listing
July 2018

Parameters of Metabolic Syndrome in Obese Children and Adolescents.

Pril (Makedon Akad Nauk Umet Odd Med Nauki) 2018 Jul;39(1):105-114

Macedonian Academy of Science and Arts, Skopje, Republic of Macedonia.

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http://dx.doi.org/10.2478/prilozi-2018-0030DOI Listing
July 2018

Growth Hormone Treatment in Children Born Small for Gestational Age (SGA).

Pril (Makedon Akad Nauk Umet Odd Med Nauki) 2018 Jul;39(1):143-149

University Children's Hospital, Medical Faculty Skopje, Republic of Macedonia.

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http://dx.doi.org/10.2478/prilozi-2018-0034DOI Listing
July 2018

Gene Alterations in Small for Gestational Age (SGA) Children.

Open Access Maced J Med Sci 2018 May 13;6(5):790-793. Epub 2018 Jun 13.

University Children's Hospital, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia.

Background: Small for gestational age children (SGA) is born on term with BW and or BL of -2.0 standard deviation score (SDS). SGA children have an increased risk of being short, developing DM, and cardiovascular and cerebrovascular disease. Often defects of are the cause of SGA. Most frequently affected part of the IGF1R gene is the exon 2.

Aim: To investigate whether the exon 2 of the gene is affected in the SGA children.

Patients And Methods: A cohort of 100 SGA children born in term was evaluated for alterations in gene. Their anthropometric parameters, IGF1 serum concentrations and IGF1 SDS values were analysed. The molecular analysis of IGF1R gene was performed by PCR restriction-site analysis and followed by direct sequencing of conspicuous fragments.

Results: Within our cohort, 64 SGA children were with short stature (height SDS -3.25 ± 0.90 SDS), and 36 were with normal height for their age and sex, (H SDS was 0.20 ± 1.1 SDS). None of these children had microcephaly (occipitofrontal circumference -0.70 ± 1.01 SDS vs 0.06 ± 0.56 SDS in SGA children with normal height) or dysmorphic features. The IGF1 serum concentrations and IGF1 SDS values of all children were within normal range. Only one child had lower normal serum IGF1 concentration. No alterations in exon 2 of gene were detected.

Conclusions: The genetic analysis of the exon 2 of the gene did not detect any gene defects in the analysed patients. The putative genetic defect in those children affects other parts of the gene or another gene (s), or yet unidentified factors.
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http://dx.doi.org/10.3889/oamjms.2018.209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985885PMC
May 2018

The Spectrum of Kidney Diseases in Children Associated with Low Molecular Weight Proteinuria.

Open Access Maced J Med Sci 2018 May 16;6(5):814-819. Epub 2018 May 16.

University Children's Hospital, Medical Faculty, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia.

Background: Proteinuria, in addition to haematuria, is the most important laboratory parameter in patients with nephro-urological diseases. Low molecular weight proteinuria (LMWP) is of particular importance because some diseases genetic and tubulointerstitial are diagnosed based on its presence.

Aim: The purpose of this study is to describe the clinical features, the course and outcome of pediatric patients with a renal disease associated with LMWP.

Material And Methods: This retrospective observational study included 250 pediatric patients with various kidney diseases in which the type of proteinuria was defined by 4-20% gradient gel sodium dodecyl sulphate polyacrylamide gel (SDS-PAG) electrophoresis.

Results: Isolated LMWP was detected in 12% of patients, while mixed glomerulotubular proteinuria was detected in 18% of patients. It was detected in all patients with the Dent-1/2 disease, Lowe's syndrome and secondary Fanconi syndrome. Transient LMWP was also detected in a series of 12 patients with distal renal tubular acidosis. In patients with nephrotic syndrome, it was associated with corticoresistence and unfavourable clinical course.

Conclusion: This study contributes to the understanding of the clinical spectrum of various kidney diseases associated with LMWP, their natural course, and the effect of therapy.
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http://dx.doi.org/10.3889/oamjms.2018.221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985860PMC
May 2018

The 6th Rare Disease South Eastern Europe (See) Meeting, Skopje, Macedonia (November 11th, 2017).

Pril (Makedon Akad Nauk Umet Odd Med Nauki) 2017 Dec;38(3):163-168

Macedonian Academy of Science and Arts, Skopje, Republic of Macedonia.

The sixth SEE meeting on rare diseases (RDs) was held in MASA the November 10th, 2017. A block of lectures on rare renal diseases started the meeting: nephrotic syndrome, Alport syndrome, atypical HUS, hypophosphatemic rickets, CAKUT were presented in all complexities. Their molecular and genetic mechanisms were discussed. The discovery of a dozen of newly genes in CAKUT, congenital overgrowth, spodilocostal dysplasia, precocious puberty has been done with collaboration of Macedonian and foreign researchers. NGS and other molecular methods in diagnosis of RDs have been presented by several presenters. The mitochondrial diseases, the novelties and importance of early discovery were comprehensively presented and discussed. The genetics and treatment of persistent neonatal hypoglcaemia were of special interest. Dysmorphic syndromes (Klippel Feil) were also presented. A session of oral electronic posters was reach and inspiring. Several lectures dealt with mucopolisaccaridoses, glycogen storage diseases and the possibilities for their diagnosis and treatment. Enzyme replacement treatement (ERT), its availability, effects (or the lack of it on the brain), intratecal ERT administration and further prospects of eventual gene treatment were comprehensively exposed and discussed. The main purposes of this traditional meeting are hopefully fulfilled: increased number of patients with RDs treated and cutting edge presentations got.
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http://dx.doi.org/10.2478/prilozi-2018-0018DOI Listing
December 2017

Rare Renal Disease in Macedonia - An Update.

Pril (Makedon Akad Nauk Umet Odd Med Nauki) 2017 Dec;38(3):63-69

Macedonia Academy of Science and Arts, Skopje, Republic of Macedonia.

Rare renal diseases (RRD) are an important category of rare disease (RD) as they can do great damage to the patients, families and society. The patient may undergo years even decades of numerous investigations including invasive procedures and yet not have definitive and precise diagnose and therefore, no opportunity for appropriate treatment. The great progress in molecular genetic techniques characterized many Mendelian diseases on molecular level. This gave the possibility for appropriate prevention and treatment interventions, genetic counseling and prenatal diagnosis. Herein, we summarize the current status of RRD in Macedonia. The research interest of Macedonian clinicians and scientists is focused on the genetics of congenital anomalies of the kidney and urinary tract (CAKUT), steroid resistant nephrotic syndrome, nephrolithiasis and nephrocalcinosis, cystic diseases and cilliopathies with collaborations with eminent laboratories in Unites States and Europe. This collaboration resulted in detection of new genes and pathophysiological pathways published in The New England Journal of Medicine and in other high impact journals. Macedonian health professionals have knowledge and equipment for diagnosis of RRD. Unfortunately the lack of finances is great obstacle for early and appropriate diagnosis. Participation in the international registries, studies and trials should be encouraged. This would result in significant benefit for the patients, health professionals and science.
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http://dx.doi.org/10.2478/prilozi-2018-0007DOI Listing
December 2017

Obesity in Childhood and Adolescence, Genetic Factors.

Pril (Makedon Akad Nauk Umet Odd Med Nauki) 2017 Dec;38(3):121-133

Faculty of Medicine, University "Ss. Cyril and Methodius", 50 Divizija BB,1000 Skopje, Republic of Macedonia.

Obesity and excess weight are a pandemic phenomenon in the modern world. Childhood and adolescent obesity often ends up in obesity in adults. The costs of obesity and its consequences are staggering for any society, crippling for countries in development. Childhood obesity is also widespread in Macedonia. Metabolic syndrome, dyslipidemia and carbohydrate intolerance are found in significant numbers. Parents and grandparents are often obese. Some of the children are either dysmorphic, or slightly retarded. We have already described patients with Prader-Willi syndrome, Bardet-Biedl syndrome or WAGR syndrome. A genetic screening for mutations in monogenic obesity in children with early, rapid-onset or severe obesity, severe hyperphagia, hypogonadism, intestinal dysfunction, hypopigmentation of hair and skin, postprandial hypoglycaemia, diabetes insipidus, abnormal leptin level and coexistence of lean and obese siblings in the family discovers many genetic forms of obesity. There are about 30 monogenic forms of obesity. In addition, obesity is different in ethnic groups, and the types of monogenic obesity differ. In brief, an increasing number of genes and genetic mechanisms in children continue to be discovered. This sheds new light on the molecular mechanisms of obesity and potentially gives a target for new forms of treatment.
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http://dx.doi.org/10.2478/prilozi-2018-0013DOI Listing
December 2017

50 Years of the Macedonian Academy of Sciences and Arts 1967-2017 and 48 Years of Publishing the Journal Prilozi (Contributions) of MASA.

Pril (Makedon Akad Nauk Umet Odd Med Nauki) 2017 Dec;38(3):5-8

University Children's Hospital, Medical Faculty, Skopje, Republic of Macedonia.

Papers on medical subjects have been published since the first issue of the journal Prilozi in 1969, totalling a number of of 957 (nine hundred and fifty seven) papers have been published in Prilozi. Two hundred and twenty nine cover subjects on natural sciences and mathematics, and 728 (seven hundred and twenty eight) subjects on medical sciences. So far, 2017 No. XXXVIII-2, 622 (six hundred and twenty two) papers published in Prilozi are in Pubmed. Prilozi is published three times a year and it is covered by the following services: Baidu Scholar, Case, Celdes, CNKI Scholar (China National Knowledge Infrastructure), CNPIEC, DOAJ (Directory of Open Access Journals), EBSCO (relevant databases), EBSCO Discovery Service, Elsevier - SCOPUS, Google Scholar, J-Gate, JournalTOCs, KESLI-NDSL (Korean National Discovery for Science Leaders), Naviga (Softweco), Primo Central (ExLibris), Publons, PubMed, ReadCube, ResearchGate, SCImago (SJR), Summon (Serials Solutions/ProQuest), TDNet, Ulrich's Periodicals Directory/ulrichsweb WanFang Data, WorldCat (OCLC).
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http://dx.doi.org/10.2478/prilozi-2018-0001DOI Listing
December 2017

Metabolic Profiles in Obese Children and Adolescents with Insulin Resistance.

Open Access Maced J Med Sci 2018 Mar 14;6(3):511-518. Epub 2018 Mar 14.

University Clinic of Child Diseases, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia.

Background: In the past several decades, the increasing frequency of overweight and obese children and adolescents in the world has become a public health problem. It has contributed significantly to the already high tide of diabetes, cardiovascular and cerebrovascular diseases.

Aim: To investigate the frequency of insulin resistance and to evaluate the metabolic profile of insulin resistant and non-insulin resistant obese children and adolescents.

Subjects And Methods: The study included 96 (45 boys, 51 girls) obese children and adolescents aged 4-17 years old (10.50 ± 2.87 years). Only participants with Body Mass Index ≥ 95 percentile were included. We analysed sera for fasting insulin levels (FI), fasting serum triglycerides (TG), total serum cholesterol (TC), fasting plasma glucose (FPG) and plasma glucose 2 hours after the performance of the oral glucose tolerance test (2-h G). Homeostatic model assessment for insulin resistance (HOMA-IR) index was calculated as fasting insulin concentration (microunits per millilitre) x fasting glucose concentration (millimolar)/22.5. The value of HOMA-IR above 3.16 was used as a cut-off value for both genders.

Results: Insulin resistance was determined in 58.33% of study participants. Insulin resistant participants had significantly higher level of 2-h G (p = 0.02), FI level (p = 0.000) as well as TG levels (p = 0.01), compared to non-insulin resistant group. Strikingly, 70.73% of the pubertal adolescents were insulin resistant in comparison to 49.09% of the preadolescents (p = 0.03). Significantly higher percentage of insulin-resistant participants were girls (p = 0.009). Moreover, a higher percentage of the girls (70.59%) than boys (44.44%) had HOMA-IR above 3.16 and had elevated FI levels (70.59% vs 48.89%). The difference in the frequency of insulin resistance among obese versus severely obese children and adolescents was not significant (p = 0.73, p > 0.05). Our study results also showed positive, but weak, correlation of HOMA-IR with age, FPG, TG and BMI of the participants (p < 0.05).

Conclusion: Higher percentage of insulin-resistant participants was of female gender and was adolescents. In general, insulin resistant obese children and adolescents tend to have a worse metabolic profile in comparison to individuals without insulin resistance. It is of note that the highest insulin resistance was also linked with the highest concentrations of triglycerides.
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http://dx.doi.org/10.3889/oamjms.2018.097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874375PMC
March 2018

Novel Founder Mutation in Gene (c.3446_3449dupCCCT) Among Romani Patients from the Balkan Region.

Balkan Med J 2018 01;35(1):108-111

Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov", Macedonian Academy of Science and Arts, Skopje, Macedonia.

Background: Fanconi anemia is a rare autosomal recessive or X-linked disorder characterised by clinical and genetic heterogeneity. Most fanconi anemia patients harbour homozygous or double heterozygous mutations in the (60-65%), FANCC (10-15%), (~10%) or (3-6%) genes. We have already reported the variant c.190-256_283+1680del2040dupC as a founder mutation among Macedonian fanconi anemia patients of Gypsy-like ethnic origin. Here, we present a novel mutation in two patients from Macedonia and Kosovo.

Case Report: The novel mutation c.3446_3449dupCCCT was identified in two fanconi anemia patients with Romany ethnicity; a 2-year-old girl from Macedonia who is a compound heterozygote for a previously reported c.190-256_283+1680del2040dupC and the novel mutation and a 10-year-old girl from Kosovo who is a homozygote for the novel c.3446_3449dupCCCT mutation. The novel mutation is located in exon 35 in the FAAP20-binding domain which plays a crucial role in the -FAAP20 interaction and is required for integrity of the fanconi anemia pathway.

Conclusion: The finding of the c.3446_3449dupCCCT mutation in two unrelated FA patients with Romani ethnicity from Macedonia and Kosovo suggests it is a founder mutation in the Romani population living in the Balkan region.
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http://dx.doi.org/10.4274/balkanmedj.2017.0618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820438PMC
January 2018

Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis.

Kidney Int 2018 01 12;93(1):204-213. Epub 2017 Oct 12.

Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.
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http://dx.doi.org/10.1016/j.kint.2017.06.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750088PMC
January 2018

Somapacitan, a once-weekly reversible albumin-binding GH derivative, in children with GH deficiency: A randomized dose-escalation trial.

Clin Endocrinol (Oxf) 2017 Oct 8;87(4):350-358. Epub 2017 Aug 8.

Department of Women's and Children's Health, Karolinska Institutet, Pediatric Endocrinology Unit, Karolinska University Hospital, Stockholm, Sweden.

Objective: To evaluate the safety, local tolerability, pharmacodynamics and pharmacokinetics of escalating single doses of once-weekly somapacitan, a reversible, albumin-binding GH derivative, vs once-daily GH in children with GH deficiency (GHD).

Design: Phase 1, randomized, open-label, active-controlled, dose-escalation trial (NCT01973244).

Patients: Thirty-two prepubertal GH-treated children with GHD were sequentially randomized 3:1 within each of four cohorts to a single dose of somapacitan (0.02, 0.04, 0.08 and 0.16 mg/kg; n=6 each), or once-daily Norditropin SimpleXx (0.03 mg/kg; n=2 each) for 7 days.

Measurements: Pharmacokinetic and pharmacodynamic profiles were assessed.

Results: Adverse events were all mild, and there were no apparent treatment-dependent patterns in type or frequency. Four mild transient injection site reactions were reported in three of 24 children treated with somapacitan. No antisomapacitan/anti-human growth hormone (hGH) antibodies were detected. Mean serum concentrations of somapacitan increased in a dose-dependent but nonlinear manner: maximum concentration ranged from 21.8 ng/mL (0.02 mg/kg dose) to 458.4 ng/mL (0.16 mg/kg dose). IGF-I and IGFBP-3, and change from baseline in IGF-I standard deviation score (SDS) and IGFBP-3 SDS, increased dose dependently; greatest changes in SDS values were seen for 0.16 mg/kg. IGF-I SDS values were between -2 and +2 SDS, except for peak IGF-I SDS with 0.08 mg/kg somapacitan. Postdosing, IGF-I SDS remained above baseline levels for at least 1 week.

Conclusions: Single doses of once-weekly somapacitan (0.02-0.16 mg/kg) were well tolerated in children with GHD, with IGF-I profiles supporting a once-weekly treatment profile. No clinically significant safety/tolerability signals or immunogenicity concerns were identified.
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http://dx.doi.org/10.1111/cen.13409DOI Listing
October 2017

Congenital Anomalies of the Kidney and Urinary Tract in Children Born Small for Gestational Age.

Pril (Makedon Akad Nauk Umet Odd Med Nauki) 2017 Mar;38(1):53-57

University Children's Hospital Skopje, Medical Faculty Skopje.

Introduction: Congenital anomalies of the kidney and urinary tract (CAKUT) represent several types of malformations with occurrence of 1 in about 500 live births.

Objective: Small for gestation age (SGA) may influence in prevalence of CAKUT and progression of chronic kidney disease (CKD) in children. The aim of this study was to elaborate our experiences with detected CAKUT in a cohort of SGA born children in Macedonia.

Methods: Our cohort consisted of 100 SGA born children investigated for associated congenital anomalies of urinary tract. We analyzed anthropometric and clinical birth data in children with diagnosed CAKUT and estimated the stage and time of onset of CKD by biochemical and imaging technics.

Results: We revealed 7 (7.0%) SGA born children with congenital anomalies of the urinary tract. Their mean birth weight was very low 1855 gr (-3.93 SDS) and the birth length 45.57cm (-2.17 SDS), as well. A significant growth failure with reduced weight and BMI were noticed at the time of diagnosis. A diagnosis of CAKUT in 4/7 was established in the first few months of life, but in others 3 later in early childhood. Three children revealed with unilateral kidney agenesis, 2 had hypo-dysplastic kidneys and in 2 children was found vesicoureteral reflux. Normal glomerular filtration rate was estimated in 2 children with CAKUT. Stage 2 CKD with GFR 60-90 ml/minx1.73m2 had 3 children, 1 patient was graded in stage 3 and one child needed kidney transplantation, stage 5 CKD.

Conclusions: We presented 7 SGA born children with CAKUT. An early recognition, assessment and treatment of these anomalies might improve their quality of life.
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http://dx.doi.org/10.1515/prilozi-2017-0007DOI Listing
March 2017

5th Rare Disease South Eastern Europe (SEE) Meeting, Skopje, Macedonia (November 15th, 2016).

Pril (Makedon Akad Nauk Umet Odd Med Nauki) 2017 Mar;38(1):119-123

Macedonian Academy of Sciences and Arts, Bul. Krste Misirkov, No. 2, Skopje.

The fifth SEE meeting on rare diseases (RDs) was held in Macedonian Academy of Sciences and Arts (MASA) the November 11th, 2016. Several lectures dealt with mucopolysaccharidosis, glycogen storage diseases and the possibilities for their diagnosis and treatment. Enzyme replacement treatment (ERT), its availability, effects (or the lack of it) on the brain, and further prospects of eventual gene treatment were comprehensively exposed and discussed. Special accent was on Gaucher, Morquio IVA, Hunter and the audience was given new knowledge on the complexities of diagnosis and treatment. A block of lectures on rare renal diseases was also impressive. From renal stones, their molecular and genetic mechanisms to different forms of CAKUT the use of NGS and other molecular methods in diagnosis of RDs. Mitochondrial diseases, the novelties and importance of early discovery were comprehensively exposed. Special lecture was given on the complement system. Endocrine disruptors, microprolactinomas were also the topic of the meeting. A rather reach session of posters was also presented.
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http://dx.doi.org/10.1515/prilozi-2017-0016DOI Listing
March 2017

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome.

N Engl J Med 2017 02 25;376(8):742-754. Epub 2017 Jan 25.

From the Division of Nephrology (E.L.-R., M.V., V.P.C., Z.Y., A.M., J.M., N.J.S., D.A.F., R.D., M.W., G.S.M., M.B., J.M.B., K.K., A.G.G., S.S.-C.) and the Division of Nephrology in Medicine and Zuckerman Mind Brain Behavior Institute (B.H.), the Departments of Systems Biology (D.S.P., B.H.), Biochemistry and Molecular Biophysics (B.H.), and Pathology (V.D.), and the Howard Hughes Medical Institute (D.S.P., B.H.), Columbia University, and the Department of Genetics and Development, Columbia University Medical Center (Q.L., V.E.P.), New York, and the Department of Genetics, Albert Einstein College of Medicine, Bronx (S.E.R., B.E.M.) - all in New York; the Center for Human Disease Modeling, Duke University, Durham, NC (Y.P.L., B.R.A., N. Katsanis); the Departments of Internal Medicine-Nephrology (E.A.O.) and Pediatrics-Nephrology (M.G.S., C.E.G., V.V.-W.), University of Michigan School of Medicine, Ann Arbor; the Department of Anatomy, Histology, and Embryology, School of Medicine, University of Split (K.V., M.S.-B.), and the Departments of Pediatrics (A.A., M. Saraga) and Pathology (N. Kunac), University Hospital of Split, Split, Croatia; the Department of Pediatric Nephrology, VU University Medical Center, Amsterdam (R.W., J.A.E.W.); the Department of Medicine, Boston Children's Hospital (A.V., F.H.), and Harvard Medical School, Boston (A.V., F.H., I.A.D.), and the Nephrology Division, Massachusetts General Hospital, Charlestown (I.A.D.) - all in Massachusetts; the Division of Nephrology, Dialysis, Transplantation, and Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Genoa (M.B., A.C., G.M.G.), the Department of Clinical and Experimental Medicine, University of Parma (M.B., M. Maiorana, L.A.), and the Pediatric Surgery Unit, University Hospital of Parma (E.C.), Parma, the Section of Nephrology, Department of Emergency and Organ Transplantation, University of Bari, Bari (L.G.), the Department of Medical Sciences, University of Milano, and Institute of Biomedical Technologies, Italian National Institute of Research ITB-CNR, Milan (D.C.), and Dipartimento Ostetrico-Ginecologico e Seconda Divisione di Nefrologia ASST Spedali Civili e Presidio di Montichiari (C.I.) and Cattedra di Nefrologia, Università di Brescia, Seconda Divisione di Nefrologia Azienda Ospedaliera Spedali Civili di Brescia Presidio di Montichiari (F.S.), Brescia - all in Italy; the Department of General and Transplant Surgery, University Hospital of Heidelberg, Germany (V.J.L.); the Department of Pediatric Nephrology, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (R.S., L.H., C.J.), INSERM UMR 1163, Laboratory of Hereditary Kidney Diseases (R.S.), Necker-Enfants Malades Hospital, Paris Descartes-Sorbonne Paris Cite University, Imagine Institute (R.S.), Sorbonne Universités, UPMC 06, Plateforme Post-génomique de la Pitié-Salpêtrière, UMS 2 Omique, Inserm US029 (W.C.), Paris, and the Department of Genetics, Centre Hospitalier Universitaire de Reims, Unité de Formation et de Recherche de Médecine, Reims (D.G.) - both in France; the Department of Neurology, University of Washington School of Medicine, and Northwest VA Parkinson's Disease Research, Education and Clinical Centers, Seattle (A. Samii); the Division of Human Genetics, Department of Pediatrics, 22q and You Center, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania (D.M.M.-M., T.B.C., E.H.Z., S.L.F.), Division of Nephrology, Children's Hospital of Philadelphia (S.L.F.), and the Department of Genetics, University of Pennsylvania (H.H.), Philadelphia; the Dialysis Unit, Jagiellonian University Medical College (D.D.), and the Department of Pediatric Nephrology, Jagiellonian University Medical College (M. Miklaszewska), Krakow, the Department of Pediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, Lodz (M.T.), the Department of Pediatric Nephrology Medical University of Lublin, Lublin (P.S.), the Department of Pediatrics, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice (M. Szczepanska), the Department of Pediatrics and Nephrology, Medical University of Warsaw, Warsaw (M.M.-W., G.K., A. Szmigielska), and Krysiewicza Children's Hospital (M.Z.) and the Department of Medical Genetics, Poznan University of Medical Sciences, and Center for Medical Genetics GENESIS (A.L.-B., A.M.-K.), Poznań - all in Poland; the Department of Clinical Genetics (J.M.D., D.B.), National Children's Research Centre (J.M.D., P.P.), and University College Dublin School of Medicine (D.B.), Our Lady's Children's Hospital Crumlin, and the National Children's Hospital Tallaght (P.P.), Dublin, Ireland; the Division of Pediatric Nephrology, Children's Mercy Hospital, Kansas City, MO (B.A.W.); University Children's Hospital, Medical Faculty of Skopje, Skopje, Macedonia (Z.G., V.T.); Faculty of Medicine, Palacky University, Olomouc, Czech Republic (H.F.); the Division of Pediatric Nephrology, University of New Mexico Children's Hospital, Albuquerque (C.S.W.); Ben May Department for Cancer Research, University of Chicago, Chicago (A.I.); and the Department of Genetics, Howard Hughes Medical Institute, and Yale Center for Mendelian Genomics, Yale University, New Haven, CT (R.P.L.).

Background: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown.

Methods: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice.

Results: We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies.

Conclusions: We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).
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http://dx.doi.org/10.1056/NEJMoa1609009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559731PMC
February 2017

Long-term renal outcome in children with OCRL mutations: retrospective analysis of a large international cohort.

Nephrol Dial Transplant 2018 01;33(1):85-94

University College London, Institute of Child Health and Great Ormond Street Hospital for Children, National Health Service Trust, London, UK.

Background: Lowe syndrome (LS) and Dent-2 disease (DD2) are disorders associated with mutations in the OCRL gene and characterized by progressive chronic kidney disease (CKD). Here, we aimed to investigate the long-term renal outcome and identify potential determinants of CKD and its progression in children with these tubulopathies.

Methods: Retrospective analyses were conducted of clinical and genetic data in a cohort of 106 boys (LS: 88 and DD2: 18). For genotype-phenotype analysis, we grouped mutations according to their type and localization. To investigate progression of CKD we used survival analysis by Kaplan-Meier method using stage 3 CKD as the end-point.

Results: Median estimated glomerular filtration rate (eGFR) was lower in the LS group compared with DD2 (58.8 versus 87.4 mL/min/1.73 m2, P < 0.01). CKD stage II-V was found in 82% of patients, of these 58% and 28% had moderate-to-severe CKD in LS and DD2, respectively. Three patients (3%), all with LS, developed stage 5 of CKD. Survival analysis showed that LS was also associated with a faster CKD progression than DD2 (P < 0.01). On multivariate analysis, eGFR was dependent only on age (b = -0.46, P < 0.001). Localization, but not type of mutations, tended to correlate with eGFR. There was also no significant association between presence of nephrocalcinosis, hypercalciuria, proteinuria and number of adverse clinical events and CKD.

Conclusions: CKD is commonly found in children with OCRL mutations. CKD progression was strongly related to the underlying diagnosis but did not associate with clinical parameters, such as nephrocalcinosis or proteinuria.
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http://dx.doi.org/10.1093/ndt/gfw350DOI Listing
January 2018