Publications by authors named "Godelieve Morel"

7 Publications

  • Page 1 of 1

Growth charts in Cockayne syndrome type 1 and type 2.

Eur J Med Genet 2021 Jan 20;64(1):104105. Epub 2020 Nov 20.

Service de Pédiatrie 1, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Laboratoire de Génétique médicale, INSERM U1112, Institut de génétique médicale d'Alsace, Faculté de Médecine de Strasbourg, Hôpitaux Universitaires de Strasbourg, France.

Cockayne syndrome (CS) is a multisystem degenerative disorder divided in 3 overlapping subtypes, with a continuous phenotypic spectrum: CS2 being the most severe form, CS1 the classical form and CS3 the late-onset form. Failure to thrive and growth difficulties are among the most consistent features of CS, leaving affected individuals vulnerable to numerous medical complications, including adverse effects of undernutrition, abrupt overhydration and overfeeding. There is thus a significant need for specific growth charts. We retrospectively collected growth parameters from genetically-confirmed CS1 and CS2 patients, used the GAMLSS package to construct specific CS growth charts compared to healthy children from WHO and CDC databases. Growth data were obtained from 88 CS patients with a total of 1626 individual growth data points. 49 patients were classified as CS1 and 39 as CS2 with confirmed mutations in CSB/ERCC6, CSA/ERCC8 or ERCC1 genes. Individuals with CS1 initially have normal growth parameters; microcephaly occurs from 2 months whereas onset of weight and height restrictions appear later, between 5 and 22 months. In CS2, growth parameters are already below standard references at birth or drop below the 5th percentile before 3 months. Microcephaly is the first parameter to show a delay, appearing around 2 months in CS1 and at birth in CS2. Height and head circumference are more severely affected in CS2 compared to CS1 whereas weight curves are similar in CS1 and CS2 patients. These new growth charts will serve as a practical tool to improve the nutritional management of children with CS.
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http://dx.doi.org/10.1016/j.ejmg.2020.104105DOI Listing
January 2021

Mandibular-pelvic-patellar syndrome is a novel PITX1-related disorder due to alteration of PITX1 transactivation ability.

Hum Mutat 2020 09 15;41(9):1499-1506. Epub 2020 Jul 15.

Service de Génétique, Centre de Référence Anomalies du Développement et Centre de Compétences Maladies Osseuses Constitutionnelles, Hospices Civils de Lyon, Bron, France.

PITX1 is a homeobox transcription factor essential for hindlimb morphogenesis. Two PITX1-related human disorders have been reported to date: PITX1 ectopic expression causes Liebenberg syndrome, characterized by malformation of upper limbs showing a "lower limb" appearance; PITX1 deletions or missense variation cause a syndromic picture including clubfoot, tibial hemimelia, and preaxial polydactyly. We report two novel PITX1 missense variants, altering PITX1 transactivation ability, in three individuals from two unrelated families showing a distinct recognizable autosomal dominant syndrome, including first branchial arch, pelvic, patellar, and male genital abnormalities. This syndrome shows striking similarities with the Pitx1-/- mouse model. A partial phenotypic overlap is also observed with Ischiocoxopodopatellar syndrome caused by TBX4 haploinsufficiency, and with the phenotypic spectrum caused by SOX9 anomalies, both genes being PITX1 downstream targets. Our study findings expand the spectrum of PITX1-related disorders and suggest a common pattern of developmental abnormalities in disorders of the PITX1-TBX4-SOX9 signaling pathway.
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http://dx.doi.org/10.1002/humu.24070DOI Listing
September 2020

Single-fiber studies for assigning pathogenicity of eight mitochondrial DNA variants associated with mitochondrial diseases.

Hum Mutat 2020 08 12;41(8):1394-1406. Epub 2020 Jun 12.

Department of Medical Genetics, National Center for Mitochondrial Diseases, Nice Teaching Hospital, Nice, France.

Whole mitochondrial DNA (mtDNA) sequencing is now systematically used in clinical laboratories to screen patients with a phenotype suggestive of mitochondrial disease. Next Generation Sequencing (NGS) has significantly increased the number of identified pathogenic mtDNA variants. Simultaneously, the number of variants of unknown significance (VUS) has increased even more, thus challenging their interpretation. Correct classification of the variants' pathogenicity is essential for optimal patient management, including treatment and genetic counseling. Here, we used single muscle fiber studies to characterize eight heteroplasmic mtDNA variants, among which were three novel variants. By applying the pathogenicity scoring system, we classified four variants as "definitely pathogenic" (m.590A>G, m.9166T>C, m.12293G>A, and m.15958A>T). Two variants remain "possibly pathogenic" (m.4327T>C and m.5672T>C) but should these be reported in a different family, they would be reclassified as "definitely pathogenic." We also illustrate the contribution of single-fiber studies to the diagnostic approach in patients harboring pathogenic variants with low level heteroplasmy.
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http://dx.doi.org/10.1002/humu.24037DOI Listing
August 2020

Outcomes of 4 years of molecular genetic diagnosis on a panel of genes involved in premature aging syndromes, including laminopathies and related disorders.

Orphanet J Rare Dis 2019 12 11;14(1):288. Epub 2019 Dec 11.

Department of Medical Genetics, Assistance Publique Hopitaux de Marseille, Marseille, France.

Background: Segmental progeroid syndromes are a heterogeneous group of rare and often severe genetic disorders that have been studied since the twentieth century. These progeroid syndromes are defined as segmental because only some of the features observed during natural aging are accelerated.

Methods: Since 2015, the Molecular Genetics Laboratory in Marseille La Timone Hospital proposes molecular diagnosis of premature aging syndromes including laminopathies and related disorders upon NGS sequencing of a panel of 82 genes involved in these syndromes. We analyzed the results obtained in 4 years on 66 patients issued from France and abroad.

Results: Globally, pathogenic or likely pathogenic variants (ACMG class 5 or 4) were identified in about 1/4 of the cases; among these, 9 pathogenic variants were novel. On the other hand, the diagnostic yield of our panel was over 60% when the patients were addressed upon a nosologically specific clinical suspicion, excepted for connective tissue disorders, for which clinical diagnosis may be more challenging. Prenatal testing was proposed to 3 families. We additionally detected 16 variants of uncertain significance and reclassified 3 of them as benign upon segregation analysis in first degree relatives.

Conclusions: High throughput sequencing using the Laminopathies/ Premature Aging disorders panel allowed molecular diagnosis of rare disorders associated with premature aging features and genetic counseling for families, representing an interesting first-level analysis before whole genome sequencing may be proposed, as a future second step, by the National high throughput sequencing platforms ("Medicine France Genomics 2025" Plan), in families without molecular diagnosis.
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http://dx.doi.org/10.1186/s13023-019-1189-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907233PMC
December 2019

Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals.

Genet Med 2020 01 31;22(1):181-188. Epub 2019 Jul 31.

Service de génétique médicale, CHU de Nantes, Nantes, France.

Purpose: Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype-phenotype correlations in KS individuals from a registry.

Methods: Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis.

Results: Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027).

Conclusion: The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.
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http://dx.doi.org/10.1038/s41436-019-0623-xDOI Listing
January 2020

A new mutation in the mitochondrial tRNA gene associated with early-onset neuromuscular phenotype and ragged-red fibers.

Neuromuscul Disord 2016 Dec 16;26(12):885-889. Epub 2016 Sep 16.

Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, France; Nice Sophia-Antipolis University, IRCAN, CNRS, INSERM, UMR 7284 & U1081, 06107 Nice, France. Electronic address:

An 11-year-old boy with psychomotor delay, exercise intolerance, ptosis and growth delay had a muscle biopsy showing typical mitochondrial alterations (60% of ragged-red fibers and 90% of cytochrome-c oxidase-deficient fibers). Next-generation sequencing revealed a novel heteroplasmic mutation (m.15958A>T) in the MTTP gene that encodes tRNA. The mutation was not present in the accessible non-muscle tissues of the patient's asymptomatic mother. Mutations in the rarely affected MTTP gene are responsible for different clinical presentations. We report the third early-onset case associated with a mutation in this gene. The severity of myopathy is likely related to the high mutation rate (96%) found in the patient's muscle. The clinical heterogeneity associated with MTTP mutations illustrates the value of the next-generation sequencing in routine diagnosis of mitochondrial diseases.
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http://dx.doi.org/10.1016/j.nmd.2016.09.012DOI Listing
December 2016
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