Clinical genetics

  • Article
    | Open Access

    Nail-patella syndrome (NPS) is characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma and can be caused by haploinsufficiency of LMX1B; however, not all patients harbor pathogenic LMX1B mutations. Here the authors show that loss-of-function variations in upstream enhancer sequences are responsible for a limb specific form of human NPS.

    • Endika Haro
    • , Florence Petit
    •  & Kerby C. Oberg
  • Article
    | Open Access

    Mesomelic dysplasia, a severe shortening and bending of the limb, has been linked to rearrangements in the HoxD cluster in humans and mice. Here the authors engineer a 1 Mb inversion including the HoxD gene cluster and use this model to provide a mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.

    • Christopher Chase Bolt
    • , Lucille Lopez-Delisle
    •  & Denis Duboule
  • Article
    | Open Access

    An amino acid exchange (P209L) in the human co-chaperone BAG3 gives rise to severe childhood restrictive cardiomyopathy. Here the authors describe humanized transgenic mouse models which phenocopy the disease and provide insight into the pathogenic mechanisms.

    • Kenichi Kimura
    • , Astrid Ooms
    •  & Michael Hesse
  • Article
    | Open Access

    Acheiropodia is associated with homozygous deletions in the LMBR1 gene around ZRS, an enhancer regulating SHH during limb development, but how these deletions lead to this phenotype is unknown. Here the authors use whole-genome sequencing, ChIP-seq, 4C-seq and DNA FISH to show that alterations in CTCF motifs are responsible via altered enhancer–promoter interactions.

    • Aki Ushiki
    • , Yichi Zhang
    •  & Nadav Ahituv
  • Article
    | Open Access

    eIF5A is critical for protein synthesis but has not yet been associated with congenital human disease. Here, the authors show that EIF5A variants cause a Mendelian disorder via reduced eIF5A-ribosome interactions and this phenotype is partially corrected by spermidine supplementation in yeast and zebrafish.

    • Víctor Faundes
    • , Martin D. Jennings
    •  & Siddharth Banka
  • Article
    | Open Access

    Aberrant splicing is a major contributor to rare disease, but detection accuracy using current methods is limited. Here, the authors develop an algorithm that detects aberrant splicing and intron retention events from RNA-seq data and apply it to diagnosis in mitochondrial disease.

    • Christian Mertes
    • , Ines F. Scheller
    •  & Julien Gagneur
  • Article
    | Open Access

    The role of ciliary/centriolar components in the postnatal brain is unclear. Here, the authors show via ablation of Pcm1 in mice that degenerative ciliary/centriolar phenotypes induce neuroanatomical and behavioral changes. Sequencing of PCM1 in human cohorts and zebrafish in vivo complementation suggests PCM1 mutations can contribute to schizophrenia.

    • Tanner O. Monroe
    • , Melanie E. Garrett
    •  & Nicholas Katsanis
  • Article
    | Open Access

    The human ICF 4 syndrome is caused by mutation of the chromatin remodeller LSH. Here, the authors show that LSH depletion disrupts the ability of histone variant macroH2A to insert into chromatin and silence transcription.

    • Kai Ni
    • , Jianke Ren
    •  & Kathrin Muegge
  • Article
    | Open Access

    Here, the authors perform ATAC-seq on four distinct cell populations from three different regions of the human brain, finding that chromatin accessibility varies greatly by cell type and less by brain region. This study reveals differences in biological function and gene regulation, as well as overlap of genetic variants associated with schizophrenia and other neuropsychiatric traits.

    • Mads E. Hauberg
    • , Jordi Creus-Muncunill
    •  & Panos Roussos
  • Article
    | Open Access

    Familial carpal tunnel syndrome (CTS) is common, but causal genes are not characterized. Here the authors report two CTS-related mutations in two large families that impair secretion of COMP in tenocytes, leading to ER stress-induced unfolded protein response, inflammation and fibrosis in patients and mouse models.

    • Chunyu Li
    • , Ni Wang
    •  & Bo Gao
  • Article
    | Open Access

    Around half of the heritability underpinning familial high-grade serous ovarian carcinoma remains unidentified. Here, the authors show that extremely rare protein encoding loss-of-function variants, with a high degree of genetic heterogeneity, may account for some of this missing heritability.

    • Deepak N. Subramanian
    • , Magnus Zethoven
    •  & Ian G. Campbell
  • Article
    | Open Access

    Heart failure has a heterogeneous etiology and the genetic underpinnings are not well understood. Here, Arvanitis et al. perform GWAS meta-analysis including 10,976 heart failure cases and 437,573 controls, identify new loci near ABO and ACTN2 and show that deletion of a ACTN2 enhancer leads to reduced ACTN2 expression in differentiating cardiomyocytes.

    • Marios Arvanitis
    • , Emmanouil Tampakakis
    •  & Alexis Battle
  • Article
    | Open Access

    FCH domain only 1 (FCHO1) is a key molecule involved in clathrin-mediated endocytosis (CME). Here, the authors report homozygous FCHO1 mutations in individuals with variable T and B cell lymphopenia, which are associated with loss-of-function of FCHO1 and impaired formation of clathrin-coated pits in T cells.

    • Marcin Łyszkiewicz
    • , Natalia Ziętara
    •  & Christoph Klein
  • Article
    | Open Access

    Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery.

    • Pilar Cacheiro
    • , Violeta Muñoz-Fuentes
    •  & Coleen Kane
  • Article
    | Open Access

    Aneuploidy (abnormal chromosome number) can enable rapid adaptation to stress conditions, but it also entails fitness costs from gene imbalance. Here, the authors experimentally evolve yeast while forcing maintenance of aneuploidy to identify the mechanisms that promote tolerance of aneuploidy.

    • Alaattin Kaya
    • , Marco Mariotti
    •  & Vadim N. Gladyshev
  • Article
    | Open Access

    UDP-glucuronic acid is a component of the extracellular matrix. Here, the authors report biallelic variants in the gene encoding UDP-Glucose 6-Dehydrogenase (UGDH) in individuals affected by developmental epileptic encephalopathies that impair UGDH stability, oligomerization, or enzymatic activity in vitro.

    • Holger Hengel
    • , Célia Bosso-Lefèvre
    •  & Bruno Reversade
  • Article
    | Open Access

    Down syndrome (DS) is caused by trisomy 21 (T21), but the underlying etiology of the related immune and neurological dysfunction is unclear. Here, the authors show that T21 activates the kynurenine pathway via increased interferon receptor copy number, which could contribute to DS pathophysiology.

    • Rani K. Powers
    • , Rachel Culp-Hill
    •  & Joaquin M. Espinosa
  • Article
    | Open Access

    Mosaic loss of chromosome Y (mLOY) is associated with age and smoking but also genetic factors play a role. Here, Terao et al. perform GWAS for mLOY in 95,380 Japanese men and identify 46 loci that overlap with hematopoietic stem cell enhancers and transcription factor binding sites critical for hematopoiesis.

    • Chikashi Terao
    • , Yukihide Momozawa
    •  & Yoichiro Kamatani
  • Article
    | Open Access

    Mucopolysaccharidosis type I (MPSI) is a lysosomal storage disease caused by insufficient iduronidase (IDUA) activity. Here, the authors use an ex vivo genome editing approach to overexpress IDUA in human hematopoietic stem and progenitor cells and show it can phenotypically correct MSPI in mouse model.

    • Natalia Gomez-Ospina
    • , Samantha G. Scharenberg
    •  & Matthew H. Porteus
  • Article
    | Open Access

    Adolescent idiopathic scoliosis (AIS) is a common pediatric disease leading to spinal deformities. Here, the authors report GWAS followed by genome-wide meta-analysis in up to 79,211 Japanese individuals, identifying 20 genetic loci for AIS, 14 of which were previously unreported, and perform in vitro validation for rs1978060.

    • Ikuyo Kou
    • , Nao Otomo
    •  & Shiro Ikegawa
  • Article
    | Open Access

    Systematic analysis of postzygotic mosaicism (PZM) is difficult due to challenges in detecting such events. Here, Wright et al. analyse trio exome sequencing data from blood and saliva of 4,293 probands with developmental disorders from the DDD Study and estimate that >3% of causative de novo mutations result from PZM.

    • C. F. Wright
    • , E. Prigmore
    •  & M. E. Hurles
  • Article
    | Open Access

    Many causative genes are known for epileptic or developmental and epileptic encephalopathies (EE/DEE) yet a genetic diagnosis cannot be made for many patients. Here, the authors analyse whole exome sequencing data from a Japanese case−control cohort to identify common, rare and ultra-rare coding variants associated with EE/DEE.

    • Atsushi Takata
    • , Mitsuko Nakashima
    •  & Naomichi Matsumoto
  • Article
    | Open Access

    Diagnostic filtering is an important step to analyze the functional and clinical significance of the large number of genetic variants identified from next-generation genome sequencing data. Here, the authors develop a flexible and scalable system for diagnostic filtering of genetic variants using G2P with Ensembl VEP.

    • Anja Thormann
    • , Mihail Halachev
    •  & David R. FitzPatrick
  • Review Article
    | Open Access

    Generation of transgenic mice has become routine in studying gene function and disease mechanisms, but often this is not enough to fully understand human biology. Here, the authors review the current state of the art of targeted genomic humanisation strategies and their advantages over classic approaches.

    • Fei Zhu
    • , Remya R. Nair
    •  & Thomas J. Cunningham
  • Article
    | Open Access

    The BIN1 SNP rs744373 is associated with higher CSF tau and phosphorylated tau levels. Here the authors show, using PET imaging, that this SNP is associated with tau accumulation in the brain as well as impaired memory in older individuals without dementia.

    • Nicolai Franzmeier
    • , Anna Rubinski
    •  & Ansgar J. Furst
  • Article
    | Open Access

    Loss of the cadherin FAT1 has been associated with nephropathy and epithelial cell adhesion defects. Here, the authors report five families with a syndromic form of coloboma associated with homozygous frameshift variants in FAT1 and recapitulate the phenotype in mutant mice and zebrafish.

    • Najim Lahrouchi
    • , Aman George
    •  & Abdelaziz Sefiani
  • Article
    | Open Access

    Valyl-tRNA synthetase (VARS) charges valyl-tRNA with the amino acid valine, required for translation. Here, the authors describe a progressive epileptic encephalopathy in individuals from five families carrying biallelic mutations in the VARS gene that leave the enzyme activity partially intact.

    • Jennifer Friedman
    • , Desiree E. Smith
    •  & Joseph G. Gleeson
  • Article
    | Open Access

    tRNAs are linked with their cognate amino acid by aminoacyl tRNA synthetases (ARS). Here, the authors report a developmental encephalopathy associated with biallelic VARS variants (valyl-tRNA synthetase) that lead to loss of function, as determined by several in vitro assays and a vars knockout zebrafish model.

    • Aleksandra Siekierska
    • , Hannah Stamberger
    •  & Peter De Jonghe
  • Article
    | Open Access

    Transient aneuploidy enables cells to survive sudden environmental changes before longterm cellular adaptations are established. Here, the authors show that yeast cells respond to the acute loss of Ulp2 SUMO protease by rapid induction of aneuploidy, and reveal predictable long-term adaptation mechanisms that restore euploidy.

    • Hong-Yeoul Ryu
    • , Francesc López-Giráldez
    •  & Mark Hochstrasser
  • Article
    | Open Access

    Mutations in genes encoding subunits of the BAF complex can cause Coffin–Siris and Nicolaides–Baraitser syndromes. Here the authors identify overlapping DNA methylation signatures in individuals with subtypes of these two syndromes that suggest a functional link and can be used to diagnose subjects with unclear clinical presentations.

    • Erfan Aref-Eshghi
    • , Eric G. Bend
    •  & Bekim Sadikovic
  • Article
    | Open Access

    Chromodomain Helicase DNA-binding (CHD) proteins have been implicated in neurodevelopmental processes. Here, the authors identify missense variants in CHD3 that disturb its chromatin remodeling activities and cause a neurodevelopmental disorder with macrocephaly and speech and language impairment.

    • Lot Snijders Blok
    • , Justine Rousseau
    •  & Philippe M. Campeau
  • Article
    | Open Access

    Genetic variants in ACTB and ACTG1 have been associated with Baraitser-Winter Cerebrofrontofacial syndrome. Here, the authors report of a syndromic thrombocytopenia caused by variants in ACTB exons 5 or 6 that compromise the organization and coupling of the cytoskeleton, leading to impaired platelet maturation.

    • Sharissa L. Latham
    • , Nadja Ehmke
    •  & Nataliya Di Donato
  • Article
    | Open Access

    Association between variants in 11 different genes and breast cancer risk has been established and sequencing of these genes is recommended to provide personalized diagnosis, therapy, and surveillance for the high-risk patients and their relatives. Here the authors analyse the frequency of germline pathogenic mutations in these genes specifically in a Japanese population.

    • Yukihide Momozawa
    • , Yusuke Iwasaki
    •  & Michiaki Kubo
  • Article
    | Open Access

    The majority of skeletal dysplasia are caused by pathogenic variants in genes required for glycosaminoglycan (GAG) metabolism. Here, Dubail et al. identify genetic variants in the solute carrier family protein SLC10A7 in families with skeletal dysplasia and amelogenesis imperfecta that disrupt GAG synthesis.

    • Johanne Dubail
    • , Céline Huber
    •  & Valérie Cormier-Daire
  • Article
    | Open Access

    NOD2 has been shown to be crucial for immune recognition of Aspergillus infection. Here the authors show that a common NOD2 genetic variant associated with Crohn’s disease is associated with reduced risk of disease due to enhanced antifungal activates of monocytes and macrophages.

    • Mark S. Gresnigt
    • , Cristina Cunha
    •  & Frank L. van de Veerdonk
  • Article
    | Open Access

    Historical acute promyelocytic leukemia patients treated with retinoic acid and chemotherapy sometimes did relapse. Here the authors performed exome sequencing on 64 patient's samples from diagnosis/relapse/remission and show relapse associates either with cooperating oncogenes at diagnosis, or with unexpected persistence of ancestral pre-leukemic clones.

    • Jacqueline Lehmann-Che
    • , Cécile Bally
    •  & Hugues de Thé
  • Article
    | Open Access

    ELL2 was recently discovered as a susceptibility gene for multiple myeloma (MM). Here, they show that the MM risk allele lowers ELL2 expression in plasma cells, that it also upregulates gene sets related to ribosome biogenesis, and that one of the linked variants reduces binding of MAFF/G/K family transcription factors.

    • Mina Ali
    • , Ram Ajore
    •  & Björn Nilsson
  • Article
    | Open Access

    Many SNPs associated with inflammatory bowel disease are located in non-coding genomic regions. Here, the authors perform CAGE-sequencing on descending colon biopsies of Crohn’s disease and ulcerative colitis patients to map transcription start sites and enhancer activity for analysis of regulatory regions.

    • Mette Boyd
    • , Malte Thodberg
    •  & Albin Sandelin
  • Article
    | Open Access

    Melorheostosis is characterized by bone overgrowth and associated with pain and functional impairment. Here, the authors use whole exome sequencing to identify somatic mutations in MAP2K1 in affected bone of melorheostosis patients which is associated with increased proliferation but delayed differentiation of cultured osteoblasts.

    • Heeseog Kang
    • , Smita Jha
    •  & Timothy Bhattacharyya
  • Article
    | Open Access

    The role of type I interferons in bacterial infection is less clear than it is in viral infection. Here, the authors show that genetic variation of the human IFNAR1 gene is associated with decreased susceptibility to tuberculosis and identify a role for the IFNAR1 inter-domain region in the cytokine response.

    • Guoliang Zhang
    • , Nicole A. deWeerd
    •  & Carl G. Feng
  • Article
    | Open Access

    Inborn errors of vitamin B12 metabolism of the cblC class are caused by mutations in the MMACHC gene. Here, Guéant et al. report epi-cblC, a class of cblC in which patients are compound heterozygous for a genetic mutation and a secondary epimutation at the MMACHC locus.

    • Jean-Louis Guéant
    • , Céline Chéry
    •  & David S. Rosenblatt
  • Article
    | Open Access

    Growth retardation is most commonly caused by genetic defects in the growth hormone pathway. Here, in families with growth retardation and gingival fibromatosis, the authors identify mutations in the potassium channel gene KCNQ1 that cause electrophysiological aberrations and altered ACTH secretion in vitro.

    • Johanna Tommiska
    • , Johanna Känsäkoski
    •  & Taneli Raivio
  • Article
    | Open Access

    Trisomy 21 (T21) is a major cause of Down syndrome but little is known about its impact on the cellular proteome. Here, the authors define the proteome of T21 fibroblasts and its turnover and also map proteomic differences in monozygotic T21-discordant twins, revealing extensive, organelle-specific changes caused by T21.

    • Yansheng Liu
    • , Christelle Borel
    •  & Ruedi Aebersold