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Background: We report a three-generation family with isolated Alport-like retinal abnormalities in the absence of lenticonus, hearing loss, kidney disease, and detectable molecular genetic defects in known Alport-related genes., Methods: Clinical examination includes ocular biomicroscopy, fundus photography, optical coherence tomography, dipstick urinalysis, serum creatinine assessment, and molecular genetic analysis., Results: The proband, her mother, and her maternal grandmother had normal best-corrected visual acuity and normal visual fields in both eyes. The macula presented a petaloid stair-case profile with scarce vessels in both eyes of the proband and a flat temporal macula lacking a foveal avascular zone in her mother and her grandmother. No family member had renal symptoms, unexplained subnormal hearing, or lenticonus. Sequencing and MLPA found no defect in COL4A3 , COL4A4 , and COL4A5 . Common SNPs around the genes ± 1Mb showed no segregation. Furthermore, none of the variants shared between the affected individuals in genes from a gene panel of genes relevant for ophthalmopathy nor whole exome- and genome sequencing explained the phenotype., Conclusion: A new condition with two retinal Alport-like phenotypes was found. No abnormalities of the kidneys and lens were found, neither abnormalities of the type IV collagen genes related to Alport syndrome. Homology with retinal abnormalities seen in patients after surgical removal of the inner limiting membrane of the retina suggests that this is where the defect is located. We therefore suggest that the new retinal phenotypes and similar phenotypes can be described with the new definition "frail inner limiting membrane maculopathy."

Autosomal dominant polycystic kidney disease (ADPKD) resulting from pathogenic variants in PKD1 and PKD2 is the most common form of PKD, but other genetic causes tied to primary cilia function have been identified. Biallelic pathogenic variants in the serine/threonine kinase NEK8 cause a syndromic ciliopathy with extra-kidney manifestations. Here we identify NEK8 as a disease gene for ADPKD in 12 families. Clinical evaluation was combined with functional studies using fibroblasts and tubuloids from affected individuals. Nek8 knockout mouse kidney epithelial (IMCD3) cells transfected with wild type or variant NEK8 were further used to study ciliogenesis, ciliary trafficking, kinase function, and DNA damage responses. Twenty-one affected monoallelic individuals uniformly exhibited cystic kidney disease (mostly neonatal) without consistent extra-kidney manifestations. Recurrent de novo mutations of the NEK8 missense variant p.Arg45Trp, including mosaicism, were seen in ten families. Missense variants elsewhere within the kinase domain (p.Ile150Met and p.Lys157Gln) were also identified. Functional studies demonstrated normal localization of the NEK8 protein to the proximal cilium and no consistent cilia formation defects in patient-derived cells. NEK8-wild type protein and all variant forms of the protein expressed in Nek8 knockout IMCD3 cells were localized to cilia and supported ciliogenesis. However, Nek8 knockout IMCD3 cells expressing NEK8-p.Arg45Trp and NEK8-p.Lys157Gln showed significantly decreased polycystin-2 but normal ANKS6 localization in cilia. Moreover, p.Arg45Trp NEK8 exhibited reduced kinase activity in vitro. In patient derived tubuloids and IMCD3 cells expressing NEK8-p.Arg45Trp, DNA damage signaling was increased compared to healthy passage-matched controls. Thus, we propose a dominant-negative effect for specific heterozygous missense variants in the NEK8 kinase domain as a new cause of PKD., (Copyright © 2023 International Society of Nephrology. All rights reserved.)

De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities." Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders., Competing Interests: Declaration of interests S.W.S. is a scientific consultant of Population Bio and the King Abdullaziz University, and Athena Diagnostics has licensed intellectual property from his work held by the Hospital for Sick Children, Toronto., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Developmental dysplasia of the hip (DDH) is a common condition involving instability of the hip with multifactorial etiology. Early diagnosis and treatment are critical as undetected DDH is an important cause of long-term hip complications. Better diagnostics may be achieved through genetic methods, especially for patients with positive family history. Several candidate genes have been reported but the exact molecular etiology of the disease is yet unknown. In the present study, we performed whole exome sequencing of DDH patients from 28 families with at least two affected first-degree relatives. Four genes previously not associated with DDH (METTL21B, DIS3L2, PPP6R2, and TM4SF19) were identified with the same variants shared among affected family members, in more than two families. Among known association genes, we found damaging variants in DACH1, MYH10, NOTCH2, TBX4, EVC2, OTOG, and SHC3. Mutational burden analysis across the families identified 322 candidate genes, and enriched pathways include the extracellular matrix, cytoskeleton, ion-binding, and detection of mechanical stimulus. Taken altogether, our data suggest a polygenic mode of inheritance for DDH, and we propose that an impaired transduction of the mechanical stimulus is involved in the etiopathological mechanism. Our findings refine our current understanding of candidate causal genes in DDH, and provide a foundation for downstream functional studies., (© 2022. The Author(s).)

Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited., Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD., Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed., Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published., Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Autosomal recessive polycystic kidney disease is a cystic kidney disease with early onset and clinically characterized by enlarged echogenic kidneys, hypertension, varying degrees of kidney dysfunction, and liver fibrosis. It is most frequently caused by sequence variants in the PKHD1 gene, encoding fibrocystin. In more rare cases, sequence variants in DZIP1L are seen, encoding the basal body protein DAZ interacting protein 1-like protein (DZIP1L). So far, only four different DZIP1L variants have been reported., Methods: Four children from three consanguineous families presenting with polycystic kidney disease were selected for targeted or untargeted exome sequencing., Results: We identified two different, previously not reported homozygous DZIP1L sequence variants: c.193 T > C; p.(Cys65Arg), and c.216C > G; p.(Cys72Trp). Functional analyses of the c.216C > G; p.(Cys72Trp) variant indicated mislocalization of mutant DZIP1L., Conclusions: In line with published data, our results suggest a critical role of the N-terminal domain for proper protein function. Although patients with PKHD1-associated autosomal recessive polycystic kidney disease often have liver abnormalities, none of the present four patients showed any clinically relevant liver involvement. Our data demonstrate the power and efficiency of next-generation sequencing-based approaches. While DZIP1L-related polycystic kidney disease certainly represents a rare form of the disease, our results emphasize the importance of including DZIP1L in multigene panels and in the data analysis of whole-exome sequencing for cystic kidney diseases. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s).)

Genetic testing for pathogenic COL4A3-5 variants is usually undertaken to investigate the cause of persistent hematuria, especially with a family history of hematuria or kidney function impairment. Alport syndrome experts now advocate genetic testing for persistent hematuria, even when a heterozygous pathogenic COL4A3 or COL4A4 is suspected, and cascade testing of their first-degree family members because of their risk of impaired kidney function. The experts recommend too that COL4A3 or COL4A4 heterozygotes do not act as kidney donors. Testing for variants in the COL4A3-COL4A5 genes should also be performed for persistent proteinuria and steroid-resistant nephrotic syndrome due to suspected inherited FSGS and for familial IgA glomerulonephritis and kidney failure of unknown cause., (Copyright © 2022 by the American Society of Nephrology.)

The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3-5). It identified 'mutational hotspots' (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that 'well-established' functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common 'incidental' findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3-COL4A5 genes remains a challenge., (© 2021. The Author(s).)

This review covers congenital hair shaft anomalies, which are conditions affecting hair shaft morphology. Sometimes suspected with the naked eye, often in need of microscopic examination to properly diagnose, these conditions could lead to the discovery of a complex genetic syndrome. Further knowledge is needed in order to establish a diagnosis, approach treatment alternatives and shed light on prognoses, which benefits patients. Our aim is to provide an updated summary of pathogenesis, clinical findings, treatment options and prognosis as well as psychosocial impact.

Mosaicism in blood varies with age, and cross-sectional studies indicate that for women, skewness of X-chromosomal mosaicism increases with age. This pattern could, however, also be due to less X-inactivation in more recent birth cohorts. Skewed X-chromosome inactivation was here measured longitudinally by the HUMARA assay in 67 septuagenarian and octogenarian women assessed at 2 time points, 10 years apart, and in 10 centenarian women assessed at 2 time points, 2-7 years apart. Skewed X-chromosome inactivation was also compared in 293 age-matched septuagenarian twins born in 1917-1923 and 1931-1937, and 212 centenarians born in 1895, 1905 and 1915. The longitudinal study of septuagenarians and octogenarians revealed that 16% (95% CI 7-29%) of the women developed skewed X-inactivation over a 10-year period. In the cross-sectional across-birth cohort study, the earlier-born septuagenarian (1917-1923) and centenarian women (1895) had a higher degree of skewness than the respective recent age-matched birth cohorts, which indicates that the women in the more recent cohorts, after the age of 70, had not only changed degree of skewness with age, they had also undergone less age-related hematopoietic sub-clone expansion. This may be a result of improved living conditions and better medical treatment in the more recent birth cohorts.

Background: Alport syndrome is a progressive hereditary kidney disease clinically presenting with haematuria, proteinuria, and early onset end-stage renal disease, and often accompanied by hearing loss and ocular abnormalities. The inheritance is X-linked in the majority of families and caused by sequence variants in the COL4A5 gene encoding the α5-chain of type-IV collagen. The proportion of de novo COL4A5 sequence variants in X-linked Alport syndrome has been reported between 12 and 15% in previous studies., Methods: In the present study we have systematically investigated the mosaic status of asymptomatic parents of six patients with X-linked Alport syndrome using next-generation sequencing of DNA extracted from different tissues. The deleterious COL4A5 sequence variants in these patients were previously assumed to be de novo, based on Sanger sequencing of the parents., Results: A low-grade (1%) parental mosaicism was detected in only one out of six families (17%). In addition, in one out of six families (17%), we found that the mutational event probably occurred postzygotic., Conclusion: These findings highlight the importance of testing for mosaicism in unaffected parents of patients with sequence variants considered to be de novo, as it may have implications for the recurrence risk and thereby for the genetic counseling of the family., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Heterozygous variants in smooth muscle alpha-actin gene (ACTA2) are the most frequent cause of autosomal dominant hereditary thoracic aortic disease (HTAD). Several genotype-phenotype associations have been described, including a severe multisystemic smooth muscle disorder associated with de novo ACTA2 p.R179 variants, characterized by highly penetrant and early onset vascular disease, involvement of smooth muscle cell (SMC)-dependent organs and a distinct cerebrovascular phenotype. Missense variants at position 258 (p.R258C and p.R258H) have also been reported to have a more severe presentation including an increased risk for aortic dissection and a high risk of stroke. It has previously been suggested that the cerebrovascular phenotype of patients with p.R258 variants could represent a mild presentation of the cerebrovascular phenotype associated with p.R179 variants. Here we report on a five generation HTAD family with the p.R258H variant and describe the cerebrovascular findings seen in three family members, to expand on the previously reported phenotype associated with variants at this codon., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Previous studies indicate a familial predisposition for developmental dysplasia of the hip (DDH), especially among first-degree relatives. This study investigated the association between unilateral or bilateral periacetabular osteotomy (PAO), family history of DDH and the degree of relationship with relatives with DDH., Material and Methods: This cross-sectional study consisted of 815 consecutive patients undergoing PAO from 1998 to 2016. Information regarding unilateral or bilateral PAO, gender and age at the time of surgery was obtained from the clinical PAO database at Aarhus University Hospital, Denmark. A questionnaire was used to collect information about the family history of DDH. The association was assessed by logistic regression analysis, and divided into 615 unilateral and 200 bilateral PAO patients., Results: PAO patients with a first-degree relative with DDH had a 72% (odds ratio [OR] = 1.72, 95% confidence interval [CI] 1.17; 2.50) higher occurrence of bilateral PAO than patients without family relatives with DDH. This association was statistically significant ( p = 0.005), even when adjusting for gender and age at the time of surgery. A similar association was not demonstrated among any other degrees of relationship., Conclusion: Danish patients with DDH and a first-degree relative with DDH have an increased risk of being surgically treated with bilateral PAO compared to patients without a family history of DDH. Patients undergoing bilateral PAO may therefore have a strong genetic predisposition for DDH. This study reveals a potential group of patients with DDH where genetic analysis may identify relatives with a higher risk of the disease.

Background: The diagnosis of multiple sclerosis (MS) is still complicated despite improvement in diagnostic guidelines. This means that time from first symptom to diagnosis in some cases is prolonged. Many aspects of MS aetiology are unknown, but the involvement of a genetic component is well established. This is also highlighted by the occurrence of familial MS cases, which represent 10-20% of all MS cases. We hypothesize that subsequent family members in a MS family, have a shorter time from onset of disease to diagnosis compared to sporadic MS cases. To investigate this, we have conducted a register study comparing time from onset to diagnosis in familial and sporadic MS cases., Methods: This is a nationwide register study based on information from the Danish Multiple Sclerosis Registry and the Danish Civil Registration System. We included familial (first-degree relatives) and sporadic MS cases and calculated time lag between onset and diagnosis of MS for sporadic MS cases and for1st, 2nd and 3rd family members within the MS families. Median test and Cox regression were the statistical methods used to compare the familial and sporadic groups., Results: We found that 2nd and 3rd affected family member had a significant shorter time from first symptom to diagnosis compared to sporadic MS cases (2nd family member: Hazard Ratio (HR): 1.12, CI: 1.03-1.21, p = 0.007 adjusted: HR: 0.95 p = 0.22, CI 0.89-1-03 and 3rd family member HR: 1.64 CI: 1.22-2.20, p = 0.001 adjusted model: HR: 1.70, p-value: 0.000, CI: 1.32-2.18). The same difference was not seen between 1st family members and sporadic cases (HR: 1.05, CI: 0.98-1.13, p = 0.15, adjusted: 0.98, p-value: 0.53, CI: 0.91-1.05). Estimated marginal mean delay in the four groups were 4.60 years (95% CI: 4.11-5.01) in1st family members, 4.23 years (3.71-4.75) in 2nd family members, 2.11 years (0.95-3.26) in 3rd family members and 4.99 years (4.99-4.99) in sporadic MS cases., Conclusion: The 2nd and 3rd family members in MS families tend do get diagnosed faster than sporadic cases. This has implications in the diagnostic process of familial MS cases., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Primary familial brain calcification is a rare autosomal dominant or recessive neurodegenerative disease, characterized by bilateral brain calcifications in different areas of the brain. It is a clinically heterogeneous disease and patients are reported to exhibit a wide spectrum of neurological and psychiatric symptoms. Mutations in five genes have been identified so far including SLC20A2, PDGFRB, PDGFB, XPR1, and MYORG. PDGFRB encodes the platelet-derived growth factor receptor-beta, and is expressed in neurons, vascular smooth muscle cells and pericytes. Patients with a PDGFRB mutation seem to exhibit a milder phenotype and milder brain calcification on brain imaging than patients with SLC20A2 and PDGFB mutations. However, this is based on a few observations so far., Case Presentation: We present a Danish family with bilateral brain calcifications and mild clinical symptoms of primary familial brain calcification, segregating with a novel PDGFRB sequence variant: c.1834G > A; p.(Gly612Arg), detected by whole exome sequencing. The variant results in physiochemical changes at the amino acid level, and affects a highly conserved nucleotide as well as amino acid. It is located in the tyrosine kinase domain of PDGFRβ. Segregation analysis and in silico analyses predicted the missense variant to be disease causing., Conclusion: Our study confirms that PDGFRB mutation carriers in general have a mild clinical phenotype, and basal ganglia calcifications can be detected by a CT scan, also in asymptomatic mutation carriers.

Objectives: The overall distribution of disease courses in multiple sclerosis (MS) is well established, but little is known about the distribution among familial MS cases. We examine the frequency of the different MS courses among familial and sporadic MS cases and determine whether MS cases within the same family had the same age at diagnosis and have experienced the same disease course., Materials and Methods: This is a nationwide register study, based on data from the Danish MS Registry, the Danish Civil Registration System, and the Danish National Patient Registry. The main variables are MS diagnosis, MS course, and first-degree relatives with MS The statistical analyses were carried out using logistic regression analysis, Kappa coefficient, and intraclass correlations coefficient., Results: In total, 7402 MS cases were included in the study, of which 531 have an affected first-degree relatives, and 6871 are sporadic. We found that relapsing-remitting MS including secondary progressive MS was more common among familial MS cases than among sporadic MS cases (Odds ratio = 1.64, 95% CI: 1.20-2.24, P = 0.002). We subsequently analyzed data on 133 MS families and found that MS courses correlate between the first and the second MS case diagnosed, while age at diagnosis does not., Conclusion: Familial MS cases are more likely to have relapsing-remitting MS than a progressive course compared to sporadic MS cases. Secondly, we find that within MS families, first-degree relatives are likely to have the same MS course, but we do not find that they are diagnosed at the same age., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of hereditary polyneuropathies. Variants in more than 80 different genes have been associated with the disorder. In recent years, the introduction of next generation sequencing (NGS) techniques have completely changed the genetic diagnostic approach from the analysis of a handful of genes to the analysis of all genes associated with CMT in a single run. In this study we describe the CMT diagnostics in Denmark in 1992-2012, prior to the implementation of NGS, by combining laboratory- and national registry data. We investigate the effect of implementing a targeted NGS approach of 63 genes associated with CMT in the diagnostic laboratory setting. This was performed by analyzing a cohort of 195 samples from patients previously analyzed by Sanger sequencing and quantitative analysis for the common causes of CMT without reaching a molecular diagnosis. A total of 1442 CMT analyses were performed in Denmark in the period 1992-2012; a disease-causing variant was detected in 21.6% of the cases. Interestingly, the diagnosis was genetically confirmed in significantly more women than men; 25.9% compared to18.5%. In our study cohort, we found a 5.6% increase in the diagnostic yield with the introduction of a targeted NGS approach., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Klinefelter syndrome (KS) (47, XXY) is the most common sex chromosome disorder, with a prevalence of 1 in every 660 newborn males. Despite the profound adverse effects of anxiety and depression, and their greater prevalence in KS populations, no research has been conducted to date to identify the determinants of anxiety and depression among patients with KS. We examined the relationships between personality traits, social engagement, and anxiety and depression symptoms among KS patients (n = 69) and a group of male controls (n = 69) matched for age and years of education. KS patients experienced more anxiety and depression symptoms than control participants. Neuroticism was the strongest and most consistent mediator between KS and both anxiety and depression symptoms. This research suggests that neuroticism may play a central role in attention switching, anxiety and depression among patients with Klinefelter syndrome. The central role of neuroticism suggests that it may be used to help identify and treat KS patients at particularly high-risk for attention-switching deficits, anxiety and depression., Competing Interests: The authors have declared that no competing interests exist.

Klinefelter syndrome (KS) has a prevalence ranging from 85 to 250 per 100.000 newborn boys making it the most frequent sex chromosome aneuploidy in the general population. The molecular basis for the phenotypic traits and morbidity in KS are not clarified. We performed genome-wide DNA methylation profiling of leucocytes from peripheral blood samples from 67 KS patients, 67 male controls and 33 female controls, in addition to genome-wide RNA-sequencing profiling in a subset of 9 KS patients, 9 control males and 13 female controls. Characterization of the methylome as well as the transcriptome of both coding and non-coding genes identified a unique epigenetic and genetic landscape of both autosomal chromosomes as well as the X chromosome in KS. A subset of genes show significant correlation between methylation values and expression values. Gene set enrichment analysis of differentially methylated positions yielded terms associated with well-known comorbidities seen in KS. In addition, differentially expressed genes revealed enrichment for genes involved in the immune system, wnt-signaling pathway and neuron development. Based on our data we point towards new candidate genes, which may be implicated in the phenotype and further point towards non-coding genes, which may be involved in X chromosome inactivation in KS.

This document describes the application of the syntax, semantic rules, and format of the Nomenclature for Properties and Units (NPU) terminology for coded dedicated kinds-of-property in the subject field of clinical molecular genetics. A vocabulary for NPU definitions in this field, based on international terminology and nomenclature, is introduced; examples of actual NPU definitions for different types of investigations are given and explained., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Mutations in ALDH18A1 can cause autosomal recessive and dominant hereditary spastic paraplegia and autosomal recessive and dominant cutis laxa. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthetase (P5CS), which consists of two domains, the glutamate 5-kinase (G5K) and the gamma-glutamyl phosphate reductase (GR5P) domain. The location of the mutations in the gene has influence on whether the amino acid levels are affected. Mutations affecting the G5K domain have previously been found to cause reduced plasma levels of proline, citrulline and arginine, whereas such effect is not seen with mutations affecting the GR5P domain. We present a 19-year old male patient with autosomal recessive spastic paraplegia and compound heterozygosity for two ALDH18A1 mutations, one in each of the P5CS domains. This young man has spastic paraplegia with onset in childhood and temporal lobe epilepsy, but normal levels of proline, ornithine and arginine. To our knowledge, this is the first case with compound heterozygous mutations affecting both P5CS domains, where levels of plasma amino acids have been reported.

Identification of fetal kidney anomalies invites questions about underlying causes and recurrence risk in future pregnancies. We therefore investigated the diagnostic yield of next-generation sequencing in fetuses with bilateral kidney anomalies and the correlation between disrupted genes and fetal phenotypes. Fetuses with bilateral kidney anomalies were screened using an in-house-designed kidney-gene panel. In families where candidate variants were not identified, whole-exome sequencing was performed. Genes uncovered by this analysis were added to our kidney panel. We identified likely deleterious variants in 11 of 56 (20%) families. The kidney-gene analysis revealed likely deleterious variants in known kidney developmental genes in 6 fetuses and TMEM67 variants in 2 unrelated fetuses. Kidney histology was similar in the latter 2 fetuses-presenting a distinct prenatal form of nephronophthisis. Exome sequencing identified ROBO1 variants in one family and a GREB1L variant in another family. GREB1L and ROBO1 were added to our kidney-gene panel and additional variants were identified. Next-generation sequencing substantially contributes to identifying causes of fetal kidney anomalies. Genetic causes may be supported by histological examination of the kidneys. This is the first time that SLIT-ROBO signaling is implicated in human bilateral kidney agenesis., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Renal agenesis (RA) is one of the more extreme examples of congenital anomalies of the kidney and urinary tract (CAKUT). Bilateral renal agenesis is almost invariably fatal at birth, and unilateral renal agenesis can lead to future health issues including end-stage renal disease. Genetic investigations have identified several gene variants that cause RA, including EYA1 , LHX1 , and WT1 However, whereas compound null mutations of genes encoding α and γ retinoic acid receptors (RARs) cause RA in mice, to date there have been no reports of variants in RAR genes causing RA in humans. In this study, we carried out whole exome sequence analysis of two families showing inheritance of an RA phenotype, and in both identified a single candidate gene, GREB1L Analysis of a zebrafish greb1l loss-of-function mutant revealed defects in the pronephric kidney just prior to death, and F0 CRISPR/Cas9 mutagenesis of Greb1l in the mouse revealed kidney agenesis phenotypes, implicating Greb1l in this disorder. GREB1L resides in a chromatin complex with RAR members, and our data implicate GREB1L as a coactivator for RARs. This study is the first to associate a component of the RAR pathway with renal agenesis in humans., (Copyright © 2017 by the Genetics Society of America.)

The Danish Huntington's Disease Registry (DHR) is a nationwide family registry comprising 14 245 individuals from 445 Huntington's disease (HD) families of which the largest family includes 845 individuals in 8 generations. 1136 DNA and/or blood samples and 18 fibroblast cultures are stored in a local biobank. The birthplace of the oldest HD carrier in each of the 261 families of Danish origin was unevenly distributed across Denmark with a high number of families in the middle part of the peninsula Jutland and in Copenhagen, the capital. The prevalence of HD in Denmark was calculated to be 5-8:100 000. 1451 individuals in the DHR had the size of the HTT CAG repeat determined of which 975 had 36 CAG repeats or more (mean ± SD: 43,5 ± 4,8). Two unrelated individuals were compound heterozygous for alleles ≥36 CAGs, and 60 individuals from 34 independent families carried an intermediate allele., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Hall (Embryologic development and monozygotic twinning. Acta Geneticae Medicae et Gemellologiae, Vol. 45, 1996, pp. 53-57) hypothesized that chromosomal aberrations can lead to monozygotic (MZ) twinning. However, twinning and chromosomal aberrations increase prenatal mortality and could reduce the prevalence of chromosomal aberrations in live-born twins. We compared prevalence proportion ratios (PPR) of chromosomal aberrations and trisomy 21 (T21) in live-born twins versus singletons born in Denmark during 1968-2009., Methods: We linked the Danish Twin Registry and a 5% random sample of all singletons to the Danish Cytogenetic Central Register and calculated PPR adjusted for maternal age for MZ, dizygotic (DZ), and all twins versus singletons. Zygosity was based on questionnaires or genetic markers., Results: No overall difference in risk of chromosomal aberrations or T21 in twins versus singletons was found. PPR in MZ and DZ twins was 0.87 (95% CI [0.60, 1.27]) and 1.05 (95% CI [0.88, 1.27]), respectively. For T21 there was a tendency to a lower prevalence in MZ twins compared to singletons (PPR: 0.29, 95% CI [0.07, 1.14]), whereas PPR was significantly increased in DZ twins (1.62, 95% CI [1.20, 2.19]). The observed proportion of MZ twin pairs among twin pairs with aberrations (0.22, 95% CI [0.16, 0.28]) was significantly lower than the proportion expected from the Weinberg method (0.32, 95% CI [CI, 0.26, 0.39])., Conclusion: Based on databases providing complete national coverage on twins with chromosomal aberrations, we found no overall difference in risk of chromosomal aberrations or T21 in twins versus singletons. Around conception twins may have an increased risk of chromosomal aberrations, but loss of especially MZ embryos could lead to similar risk among live-born twins and singletons.