Surveillance recommendations for DICER1 pathogenic variant carriers: a report from the SIOPE Host Genome Working Group and CanGene-CanVar Clinical Guideline Working Group

AbstractDICER1 syndrome is a rare genetic disorder that predisposes to a wide spectrum of tumors. Developing surveillance protocols for this syndrome is challenging because uncertainty exists about the clinical efficacy of surveillance, and appraisal of potential benefits and harms vary. In addition, there is increasing evidence that germline DICER1 pathogenic variants are associated with lower penetrance for cancer than previously assumed. To address these issues and to harmonize DICER1 syndrome surveillance programs within Europe, the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) and Clinical Guideline Working Group of the CanGene-CanVar project in the United Kingdom reviewed current surveillance strategies and evaluated additional relevant literature. Consensus was achieved for a new surveillance protocol and information leaflet that informs patients about potential symptoms of DICER1-associated tumors. The surveillance protocol comprises a minimum program and an extended version for consideration. The key recommendations of the minimum program are: annual clinical examination from birth to age 20 years, six-monthly chest X-ray and renal ultrasound from birth to age 6 years, and thyroid ultrasound every 3 years from age 8 to age 40 years. The surveillance program for consideration comprises additional surveillance procedures, and recommendations for DICER1 pathogenic variant carriers outside the ages of the surveillance interval. Patients have to be supported in choosing the surveillance program that best meets their needs. Prospective evaluation of the efficacy and patient perspectives of proposed surveillance recommendations is required to expand the evidence base for DICER1 surveillance protocols.

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First report of X-linked hypohidrotic ectodermal dysplasia with a hemizygous c.1142G > C in the EDA gene: variant of uncertain significance or new pathogenic variant?

Italian Journal of Pediatrics ◽

10.1186/s13052-021-01078-5 ◽

2021 ◽

Vol 47 (1) ◽

Author(s):

Mario Tumminello ◽

Antonella Gangemi ◽

Federico Matina ◽

Melania Guardino ◽

Bianca Lea Giuffrè ◽

...

Keyword(s):

Ectodermal Dysplasia ◽

Genetic Disorder ◽

Missense Variant ◽

Pathogenic Variant ◽

Hypohidrotic Ectodermal Dysplasia ◽

Variant Of Uncertain Significance ◽

Uncertain Significance ◽

Clinical Potential ◽

Genomic Variant ◽

Eda Gene

Abstract Background Hypohidrotic Ectodermal Dysplasia (HED) is a genetic disorder which affects structures of ectodermal origin. X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common form of disease. XLHED is characterized by hypotrichosis, hypohydrosis and hypodontia. The cardinal features of classic HED become obvious during childhood. Identification of a hemizygous EDA pathogenic variant in an affected male confirms the diagnosis. Case presentation We report on a male newborn with the main clinical characteristics of the X-linked HED including hypotrichosis, hypodontia and hypohidrosis. Gene panel sequencing identified a new hemizygous missense variant of uncertain significance (VUS) c.1142G > C (p.Gly381Ala) in the EDA gene, located on the X chromosome and inherited from the healthy mother. Conclusion Despite the potential functional impact of VUS remains uncharacterized, our goal is to evaluate the clinical potential consequences of missense VUS on EDA gene. Even if the proband’s phenotype is characteristic for classic HED, further reports of patients with same clinical phenotype and the same genomic variant are needed to consider this novel VUS as responsible for the development of HED.

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Diagnostic and severity scores for Cockayne syndrome

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01686-8 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

M. A. Spitz ◽

F. Severac ◽

C. Obringer ◽

S. Baer ◽

N. Le May ◽

...

Keyword(s):

Early Diagnosis ◽

Severity Score ◽

Wide Spectrum ◽

Genetic Disorder ◽

Continuous Distribution ◽

Cockayne Syndrome ◽

Clinical Severity ◽

Diagnostic Score ◽

Clinical Diagnostic ◽

Severity Scores

Abstract Background Cockayne syndrome is a progressive multisystem genetic disorder linked to defective DNA repair and transcription. This rare condition encompasses a very wide spectrum of clinical severity levels ranging from severe prenatal onset to mild adult-onset subtypes. The rarity, complexity and variability of the disease make early diagnosis and severity assessment difficult. Based on similar approaches in other neurodegenerative disorders, we propose to validate diagnostic and severity scores for Cockayne syndrome. Methods Clinical, imaging and genetic data were retrospectively collected from 69 molecularly confirmed CS patients. A clinical diagnostic score and a clinical-radiological diagnostic score for CS were built using a multivariable logistic regression model with a stepwise variable selection procedure. A severity score for CS was designed on five items (head circumference, growth failure, neurosensorial signs, motor autonomy, communication skills) and validated by comparison with classical predefined severity subtypes of CS. Results Short stature, enophtalmos, hearing loss, cataracts, cutaneous photosensitivity, frequent dental caries, enamel hypoplasia, morphological abnormalities of the teeth, areflexia and spasticity were included in the clinical diagnostic score as being the most statistically relevant criteria. Appropriate weights and thresholds were assigned to obtain optimal sensitivity and specificity (95.7% and 86.4% respectively). The severity score was shown to be able to quantitatively differentiate classical predefined subtypes of CS and confirmed the continuous distribution of the clinical presentations in CS. Longitudinal follow-up of the severity score was able to reflect the natural course of the disease. Conclusion The diagnostic and severity scores for CS will facilitate early diagnosis and longitudinal evaluation of future therapeutic interventions. Prospective studies will be needed to confirm these findings.

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Current recommendations for clinical surveillance and genetic testing in rhabdoid tumor predisposition: a report from the SIOPE Host Genome Working Group

Familial Cancer ◽

10.1007/s10689-021-00229-1 ◽

2021 ◽

Author(s):

M. C. Frühwald ◽

K. Nemes ◽

H. Boztug ◽

M. C. A. Cornips ◽

D. G. Evans ◽

...

Keyword(s):

Working Group ◽

Soft Part ◽

Genetic Disorders ◽

Panel Discussion ◽

Rhabdoid Tumor ◽

Host Genome ◽

Cancer Surveillance ◽

Malignant Neoplasms ◽

Pathogenic Variants ◽

Increased Risk

AbstractThe rhabdoid tumor (RT) predisposition syndromes 1 and 2 (RTPS1 and 2) are rare genetic conditions rendering young children vulnerable to an increased risk of RT, malignant neoplasms affecting the kidney, miscellaneous soft-part tissues, the liver and the central nervous system (Atypical Teratoid Rhabdoid Tumors, ATRT). Both, RTPS1&2 are due to pathogenic variants (PV) in genes encoding constituents of the BAF chromatin remodeling complex, i.e. SMARCB1 (RTPS1) and SMARCA4 (RTPS2). In contrast to other genetic disorders related to PVs in SMARCB1 and SMARCA4 such as Coffin-Siris Syndrome, RTPS1&2 are characterized by a predominance of truncating PVs, terminating transcription thus explaining a specific cancer risk. The penetrance of RTPS1 early in life is high and associated with a poor survival. However, few unaffected carriers may be encountered. Beyond RT, the tumor spectrum may be larger than initially suspected, and cancer surveillance offered to unaffected carriers (siblings or parents) and long-term survivors of RT is still a matter of discussion. RTPS2 exposes female carriers to an ill-defined risk of small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT), which may appear in prepubertal females. RT surveillance protocols for these rare families have not been established. To address unresolved issues in the care of individuals with RTPS and to propose appropriate surveillance guidelines in childhood, the SIOPe Host Genome working group invited pediatric oncologists and geneticists to contribute to an expert meeting. The current manuscript summarizes conclusions of the panel discussion, including consented statements as well as non-evidence-based proposals for validation in the future.

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Mice with mutations in Trpm1, a gene in the locus of 15q13.3 microdeletion syndrome, display pronounced hyperactivity and decreased anxiety-like behavior

Molecular Brain ◽

10.1186/s13041-021-00749-y ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Tesshu Hori ◽

Shohei Ikuta ◽

Satoko Hattori ◽

Keizo Takao ◽

Tsuyoshi Miyakawa ◽

...

Keyword(s):

Visual Impairment ◽

Wide Spectrum ◽

Genetic Disorder ◽

Mutant Mice ◽

Chromosome 15 ◽

Microdeletion Syndrome ◽

Visual Transduction ◽

The Central Nervous System ◽

Null Mutant Mice

AbstractThe 15q13.3 microdeletion syndrome is a genetic disorder characterized by a wide spectrum of psychiatric disorders that is caused by the deletion of a region containing 7 genes on chromosome 15 (MTMR10, FAN1, TRPM1, MIR211, KLF13, OTUD7A, and CHRNA7). The contribution of each gene in this syndrome has been studied using mutant mouse models, but no single mouse model recapitulates the whole spectrum of human 15q13.3 microdeletion syndrome. The behavior of Trpm1−/− mice has not been investigated in relation to 15q13.3 microdeletion syndrome due to the visual impairment in these mice, which may confound the results of behavioral tests involving vision. We were able to perform a comprehensive behavioral test battery using Trpm1 null mutant mice to investigate the role of Trpm1, which is thought to be expressed solely in the retina, in the central nervous system and to examine the relationship between TRPM1 and 15q13.3 microdeletion syndrome. Our data demonstrate that Trpm1−/− mice exhibit abnormal behaviors that may explain some phenotypes of 15q13.3 microdeletion syndrome, including reduced anxiety-like behavior, abnormal social interaction, attenuated fear memory, and the most prominent phenotype of Trpm1 mutant mice, hyperactivity. While the ON visual transduction pathway is impaired in Trpm1−/− mice, we did not detect compensatory high sensitivities for other sensory modalities. The pathway for visual impairment is the same between Trpm1−/− mice and mGluR6−/− mice, but hyperlocomotor activity has not been reported in mGluR6−/− mice. These data suggest that the phenotype of Trpm1−/− mice extends beyond that expected from visual impairment alone. Here, we provide the first evidence associating TRPM1 with impairment of cognitive function similar to that observed in phenotypes of 15q13.3 microdeletion syndrome.

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A Novel Missense Variant in the Gene PPP2R5D Causes a Rare Neurodevelopmental Disorder with Increased Phenotype

BioMed Research International ◽

10.1155/2021/6661860 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Lulu Yan ◽

Ru Shen ◽

Zongfu Cao ◽

Chunxiao Han ◽

Yuxin Zhang ◽

...

Keyword(s):

De Novo ◽

Genetic Disorder ◽

Neurodevelopmental Disorder ◽

Three Dimensional ◽

Missense Variant ◽

Pathogenic Variant ◽

Dimensional Structure ◽

Chinese Family ◽

Speech Impairment ◽

Pathogenic Variants

PPP2R5D-related neurodevelopmental disorder, which is mainly caused by de novo missense variants in the PPP2R5D gene, is a rare autosomal dominant genetic disorder with about 100 patients and a total of thirteen pathogenic variants known to exist globally so far. Here, we present a 24-month-old Chinese boy with developmental delay and other common clinical characteristics of PPP2R5D-related neurodevelopmental disorder including hypotonia, macrocephaly, intellectual disability, speech impairment, and behavioral abnormality. Trio-whole exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variant. The pathogenicity of the variant was evaluated using bioinformatics tools. We identified a novel pathogenic variant in the PPP2R5D gene (c.620G>T, p.Trp207Leu). The variant is located in the variant hotspot region of this gene and is predicted to cause PPP2R5D protein dysfunction due to an increase in local hydrophobicity and unstable three-dimensional structure. We report a novel pathogenic variant of PPP2R5D associated with PPP2R5D-related neurodevelopmental disorder from a Chinese family. Our findings expanded the phenotypic and mutational spectrum of PPP2R5D-related neurodevelopmental disorder.

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Epileptic Encephalopathy, Myoclonus–Dystonia, and Premature Pubarche in Siblings with a Novel C-Terminal Truncating Mutation in ATRX Gene

Neuropediatrics ◽

10.1055/s-0039-1692141 ◽

2019 ◽

Vol 50 (05) ◽

pp. 327-331 ◽

Cited By ~ 1

Author(s):

Thea Giacomini ◽

Maria Stella Vari ◽

Sara Janis ◽

Giulia Prato ◽

Livia Pisciotta ◽

...

Keyword(s):

Wide Spectrum ◽

Genetic Disorder ◽

Clinical Manifestations ◽

Epileptic Seizures ◽

Epileptic Encephalopathy ◽

Recessive Mutations ◽

Truncating Mutation ◽

Alpha Thalassemia ◽

Male Patients ◽

Myoclonus Dystonia

AbstractThe X-linked alpha thalassemia mental retardation (ATR-X) syndrome is a genetic disorder caused by X-linked recessive mutations in ATRX gene, related to a wide spectrum of clinical manifestations, such as alpha thalassemia, developmental delay, genital abnormalities, and gastrointestinal disorders. Patients with ATR-X syndrome can suffer from different types of epileptic seizures, but a severe epileptic encephalopathy pattern has not been described to date. We describe, for the first time, two brothers with genetically confirmed ATR-X syndrome who presented with drug-resistant epileptic encephalopathy, with tonic and polimorphic seizures reported in the elder brother and epileptic spasms in the younger brother. Moreover, both brothers showed a peculiar movement disorder with myoclonus–dystonia, worsened during periods of distress or pain. These cases expand the clinical spectrum of ATR-X syndrome and open new opportunities for the molecular diagnosis of ATRX mutations in male patients with severe epileptic encephalopathies and movement disorders.

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Laurence Moon Bardet Biedle Syndrome

Medicine Today ◽

10.3329/medtoday.v30i1.35566 ◽

2018 ◽

Vol 30 (1) ◽

pp. 41-43

Author(s):

Md Nazrul Islam ◽

Shamima Akhter ◽

SM Kamal ◽

Sabikun Nahar Chowdhury

Keyword(s):

Retinitis Pigmentosa ◽

Clinical Features ◽

Male Patient ◽

Autosomal Recessive ◽

Wide Spectrum ◽

Genetic Disorder ◽

Learning Difficulties ◽

Multiple Systems ◽

Truncal Obesity ◽

Characteristic Features

Laurence Moon Bardet Biedle syndrome is a rare, autosomal recessive genetic disorder involving multiple systems and has wide spectrum of clinical features. Characteristic features of this disorder are retinitis pigmentosa, polydactyly, truncal obesity and learning difficulties. It may also be associated with hypogonadism in male and complex genitourinary abnormalities in female. We present a case of 33 years male patient having obesity, decreased vision, polydactyly, hypogonadism and retinitis pigmentosa. These clinical features are consistent with Laurence Moon Bardet Biedle syndrome.Medicine Today 2018 Vol.30(1): 41-43

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Genetic testing and surveillance in infantile myofibromatosis: a report from the SIOPE Host Genome Working Group

Familial Cancer ◽

10.1007/s10689-020-00204-2 ◽

2020 ◽

Author(s):

Simone Hettmer ◽

Guillaume Dachy ◽

Guido Seitz ◽

Abbas Agaimy ◽

Catriona Duncan ◽

...

Keyword(s):

Genetic Testing ◽

Working Group ◽

Host Genome ◽

Infantile Myofibromatosis

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Astronomical Units, Constants and Time-Scales

Highlights of Astronomy ◽

10.1017/s1539299600001945 ◽

1974 ◽

Vol 3 ◽

pp. 229-232

Author(s):

G. A. Wilkins

Keyword(s):

Time Scales ◽

Working Group ◽

Wide Spectrum ◽

The Other ◽

Astronomical Unit ◽

Conversion Factors ◽

Astronomical Data ◽

The Road ◽

Unit Of Length ◽

Atomic Time

As I have already reported (Trans. IAU XVA, 9, 1973), the Working Group on Units and Time-scales was not able to reach any firm conclusions on whether the concepts of the astronomical unit and ephemeris time should be retained or replaced by the SI unit of length (metre) and atomic time. This disagreement was not unexpected as the membership was deliberately chosen to cover a wide spectrum of opinion. The following comments and suggestions represent a middle-of-the-road approach that is intended to meet the requirements of most astronomers and others who use the astronomical data. It has been suggested to me that this approach is not appropriate for use in those precise applications where relativistic concepts are necessary, and that therefore we should abandon completely the use of astronomical units of mass, length and time. There are, however, many applications where Newtonian concepts are perfectly adequate, and astronomical units are widely in use because of their general suitability and convenience. We should therefore continue to define a system of astronomical units, but should state quite clearly their relationships to SI units. An individual may use either system according to the circumstances, and standard conversion factors will be available for use by those who prefer the other system.

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