Genomics

NBAS pathogenic variants: Defining the associated clinical and facial phenotype and genotype-phenotype correlations.

 
Carli D1, Giorgio E2, Pantaleoni F3, Bruselles A4, Barresi S3, Riberi E1, Licciardi F1, Gazzin A1, Baldassarre G1, Pizzi S3, Niceta M3, Radio FC3, Molinatto C1, Montin D1, Calvo PL5, Ciolfi A3, Fleischer N6, Ferrero GB1, Brusco A2,7, Tartaglia M3
 
 2019 Jun;40(6):721-728. doi: 10.1002/humu.23734. Epub 2019 Mar 18.

2019

Author information

1
Department of Public Health and Pediatrics, University of Torino, Torino, Italy.
2
Department of Medical Sciences, University of Torino, Torino, Italy.
3
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCSS, Rome, Italy.
4
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
5
Pediatric Gastroenterology Unit, Città della Salute e della Scienza University Hospital, Torino, Italy.
6
FDNA Inc, Boston, Massachusetts.
7
Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, Italy.

 

Abstract

The pathogenic variants in the neuroblastoma-amplified sequence (NBAS) are associated with a clinical spectrum involving the hepatic, skeletal, ocular, and immune systems. Here, we report on two unrelated subjects with a complex phenotype solved by whole-exome sequencing, who shared a synonymous change in NBAS that was documented to affect the transcript processing and co-occurring with a truncating change. Starting from these two cases, we systematically assessed the clinical information available for all subjects with biallelic NBAS pathogenic variants (73 cases in total). We revealed a recognizable facial profile (hypotelorism, thin lips, pointed chin, and "progeroid" appearance) determined by using DeepGestalt facial recognition technology, and we provide evidence for the occurrence of genotype-phenotype correlations. Notably, severe hepatic involvement was associated with variants affecting the NBAS-Nter and Sec39 domains, whereas milder liver involvement and immunodeficiency were generally associated with variants located at the N-terminus and C-terminus of the protein. Remarkably, no patient was reported to carry two nonsense variants, suggesting lethality of complete NBAS loss-of-function. 

 

Spontaneous remission in a Diamond-Blackfan anaemia patient due to a revertant uniparental disomy ablating a de novo RPS19 mutation

Garelli E1, Quarello P2, Giorgio E3, Carando A1, Menegatti E4,5, Mancini C3, Di Gregorio E4, Crescenzio N1, Palumbo O6, Carella M6, Dimartino P7, Pippucci T8, Dianzani I9, Ramenghi U1, Brusco A3,4
 
 2019 Jun;185(5):994-998. doi: 10.1111/bjh.15688. Epub 2018 Nov 20

Author information

1
Department of Public Health and Paediatric Sciences, University of Turin, Turin, Italy.
2
Paediatric Onco-Haematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Turin, Italy.
3
Department of Medical Sciences, University of Turin, Turin, Italy.
4
Medical Genetics Unit, "Città della Salute e della Scienza" Hospital, Turin, Italy.
5
Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
6
Division of Medical Genetics, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
7
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
8
Medical Genetics Unit, Polyclinic Sant'Orsola-Malpighi University Hospital, Bologna, Italy.
9
Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.

 

A novel case of Greenberg dysplasia and genotype–phenotype correlation analysis for LBR pathogenic variants: An instructive example of one gene‐multiple phenotypes

Giorgio E, Sirchia F, Bosco M, Sobreira NLM, Baylor-Hopkins Center for Mendelian Genomics, Grosso E, Brussino A, Brusco A. 

2019

Abstract

Greenberg skeletal dysplasia is an autosomal recessive, perinatal lethal disorder associated with biallelic variants affecting the lamin B receptor (LBR) gene. LBR is also associated with the autosomal recessive anadysplasia‐like spondylometaphyseal dysplasia, and the autosomal dominant Pelger–Huët anomaly, a benign laminopathy characterized by anomalies in the nuclear shape of blood granulocytes. The LBR is an inner nuclear membrane protein that binds lamin B proteins (LMNB1 and LMNB2), interacts with chromatin, and exerts a sterol reductase activity. Here, we report on a novel LBR missense variant [c.1379A>G; p.(D460R)], identified by whole exome sequencing and causing Greenberg dysplasia in two fetuses from a consanguineous Moroccan family. We revised published LBR variants to propose a genotype–phenotype correlation in LBR associated diseases. The diverse phenotypes are correlated to the functional domain affected, the heterozygous or homozygous state of the variants, and their different impact on the residual protein function. LBR represents an instructive example of one gene presenting with two different patterns of inheritance and at least three different clinical phenotypes.

A fetal case of microphthalmia and limb anomalies with abnormal neuronal migration associated with SMOC1 biallelic variants

Mancini C1, Zonta A2, Botta G3, Breda Klobus A4, Valbonesi S4, Pasini B2, Giorgio E1, Viora E5, Brusco A6, Brussino A1.

2019

Author information

1
University of Torino, Department of Medical Sciences, 10126, Torino, Italy.
2
Città Della Salute e Della Scienza University Hospital, Medical Genetics Unit, 10126, Torino, Italy.
3
Città Della Salute e Della Scienza University Hospital, Departments of Pathology, 10126, Torino, Italy.
4
Breda Genetics, Brescia, Italy.
5
Città Della Salute e Della Scienza University Hospital, Department of Gynecology and Obstetrics, Ultrasound and Prenatal Diagnosis Unit, 10126, Torino, Italy.
6
University of Torino, Department of Medical Sciences, 10126, Torino, Italy; Città Della Salute e Della Scienza University Hospital, Medical Genetics Unit, 10126, Torino, Italy. Electronic address: alfredo.brusco@unito.it.
 

Abstract

Microphthalmia with limb anomalies (MLA, OMIM, 206920) is a rare autosomal-recessive disease caused by biallelic pathogenic variants in the SMOC1 gene. It is characterized by ocular disorders (microphtalmia or anophtalmia) and limb anomalies (oligodactyly, syndactyly, and synostosis of the 4th and 5th metacarpals), variably associated with long bone hypoplasia, horseshoe kidney, venous anomalies, vertebral anomalies, developmental delay, and intellectual disability. Here, we report the case of a woman who interrupted her pregnancy after ultrasound scans revealed a depression of the frontal bone, posterior fossa anomalies, cerebral ventricular enlargement, cleft spine involving the sacral and lower-lumbar vertebrae, and bilateral microphthalmia. Micrognathia, four fingers in both feet and a slight tibial bowing were added to the clinical picture after fetal autopsy. Exome sequencing identified two variants in the SMOC1 gene, each inherited from one of the parents: c.709G>T - p.(Glu237*) on exon 8 and c.1223G>A - p.(Cys408Tyr) on exon 11, both predicted to be pathogenic by different bioinformatics software. Brain histopathology showed an abnormal cortical neuronal migration, which could be related to the SMOC1 protein function, given its role in cellular signaling, proliferation and migration. Finally, we summarize phenotypic and genetic data of known MLA cases showing that our case has some unique features (Chiari II malformation; focal neuropathological alterations) that could be part of the variable phenotype of SMOC1-associated diseases.

Copyright © 2018 Elsevier Masson SAS. All rights reserved.

 

Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging

Flex E1, Martinelli S2, Van Dijck A3, Ciolfi A4, Cecchetti S5, Coluzzi E6, Pannone L7, Andreoli C8, Radio FC4, Pizzi S4, Carpentieri G7, Bruselles A2, Catanzaro G9, Pedace L10, Miele E10, Carcarino E11, Ge X12, Chijiwa C13, Lewis MES13, Meuwissen M14, Kenis S15, Van der Aa N14, Larson A16, Brown K16, Wasserstein MP17, Skotko BG18, Begtrup A19, Person R19, Karayiorgou M20, Roos JL21, Van Gassen KL22, Koopmans M22, Bijlsma EK23, Santen GWE23, Barge-Schaapveld DQCM23, Ruivenkamp CAL23, Hoffer MJV23, Lalani SR24, Streff H24, Craigen WJ24, Graham BH25, van den Elzen APM26, Kamphuis DJ27, Õunap K28, Reinson K28, Pajusalu S29, Wojcik MH30, Viberti C31, Di Gaetano C31, Bertini E4, Petrucci S32, De Luca A33, Rota R10, Ferretti E34, Matullo G31, Dallapiccola B4, Sgura A6, Walkiewicz M35, Kooy RF36, Tartaglia M37

 

 
 2019 Sep 5;105(3):493-508. doi: 10.1016/j.ajhg.2019.07.007. Epub 2019 Aug 22.

 

Author information

1
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, 00161 Italy; Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY 10467, USA.
2
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, 00161 Italy.
3
Department of Medical Genetics, University of Antwerp, Edegem, 2650 Belgium; Department of Neurology, Antwerp University Hospital, Edegem, 2650 Belgium.
4
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, 00146 Italy.
5
Microscopy Area, Core Facilities, Istituto Superiore di Sanità, Rome, 00161 Italy.
6
Department of Science, University Roma Tre, Rome, 00146 Italy.
7
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, 00161 Italy; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, 00146 Italy.
8
Department of Environment and Health, Istituto Superiore di Sanità, Rome, 00161 Italy.
9
Department of Experimental Medicine, Sapienza University, Rome, 00161 Italy.
10
Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, 00146 Italy.
11
Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, 00146 Italy; Current affiliation: Cordeliers Research Centre, Inserm 1138, Sorbonne Université, Paris, 75006 France.
12
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Current affiliation: Department of Genetics and Genomic Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
13
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada.
14
Department of Medical Genetics, University of Antwerp, Edegem, 2650 Belgium.
15
Department of Neurology, Antwerp University Hospital, Edegem, 2650 Belgium.
16
Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
17
Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY 10467, USA.
18
Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02114, USA.
19
GeneDx, Gaithersburg, MD 20877, USA.
20
Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA.
21
Department of Psychiatry, University of Pretoria, Weskoppies Hospital, Pretoria, 0001 South Africa.
22
Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, 3508 AB the Netherlands.
23
Department of Clinical Genetics, Leiden University Medical Center, Leiden, 2300 RC the Netherlands.
24
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
25
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
26
Departement of Pediatrics, Reinier de Graaf Ziekenhuis, Delft, 2600 GA the Netherlands.
27
Departement of Neurology, Reinier de Graaf Ziekenhuis, Delft, 2600 GA the Netherlands.
28
Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, 50406 Estonia; Institute of Clinical Medicine, University of Tartu, Tartu, 50406 Estonia.
29
Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, 50406 Estonia; Institute of Clinical Medicine, University of Tartu, Tartu, 50406 Estonia; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
30
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
31
Department of Medical Sciences, University of Turin, Turin, 10126 Italy; Italian Institute for Genomic Medicine, Turin, 10126 Italy.
32
Department of Clinical and Molecular Medicine, Sapienza University, Rome, 00189 Italy; Division of Medical Genetics, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, 71013 Italy.
33
Division of Medical Genetics, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, 71013 Italy.
34
Department of Experimental Medicine, Sapienza University, Rome, 00161 Italy; Istituto Neuromed, IRCCS, Pozzilli, 86077 Italy.
35
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Current affiliation: National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA.
36
Department of Medical Genetics, University of Antwerp, Edegem, 2650 Belgium. Electronic address: frank.kooy@uantwerpen.be.
37
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, 00146 Italy. Electronic address: marco.tartaglia@opbg.net.

 

Abstract

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.

Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

 

 

 

 

 

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