Publications by authors named "Caroline Michot"

40 Publications

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

Geleophysic and acromicric dysplasias: natural history, genotype-phenotype correlations, and management guidelines from 38 cases.

Genet Med 2021 Feb 21;23(2):331-340. Epub 2020 Oct 21.

Fédération de Génétique médicale, Centre de référence pour les maladies osseuses constitutionnelles AP-HP, Hôpital Necker-Enfants malades, Paris, France.

Purpose: Geleophysic dysplasia (GD) and acromicric dysplasia (AD) are characterized by short stature, short extremities, and progressive joint limitation. In GD, cardiorespiratory involvement can result in poor prognosis. Dominant variants in the FBN1 and LTBP3 genes are responsible for AD or GD, whereas recessive variants in the ADAMTSL2 gene are responsible for GD only. The aim of this study was to define the natural history of these disorders and to establish genotype-phenotype correlations.

Methods: This monocentric retrospective study was conducted between January 2008 and December 2018 in a pediatric tertiary care center and included patients with AD or GD with identified variants (FBN1, LTBP3, or ADAMTSL2).

Results: Twenty-two patients with GD (12 ADAMTSL2, 8 FBN1, 2 LTBP3) and 16 patients with AD (15 FBN1, 1 LTBP3) were included. Early death occurred in eight GD and one AD. Among GD patients, 68% presented with heart valve disease and 25% developed upper airway obstruction. No AD patient developed life-threatening cardiorespiratory issues. A greater proportion of patients with either a FBN1 cysteine variant or ADAMTSL2 variants had a poor outcome.

Conclusion: GD and AD are progressive multisystemic disorders with life-threatening complications associated with specific genotype. A careful multidisciplinary follow-up is needed.
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http://dx.doi.org/10.1038/s41436-020-00994-xDOI Listing
February 2021

TAR syndrome: Clinical and molecular characterization of a cohort of 26 patients and description of novel noncoding variants of RBM8A.

Hum Mutat 2020 Jul 6;41(7):1220-1225. Epub 2020 Apr 6.

Clinical Genetics Department, Reference Center for Developmental Anomalies, CHU Lille, Lille, France.

Thrombocytopenia-absent radius (TAR) syndrome is characterized by radial defect and neonatal thrombocytopenia. It is caused by biallelic variants of RBM8A gene (1q21.1) with the association of a null allele and a hypomorphic noncoding variant. RBM8A encodes Y14, a core protein of the exon junction complex involved in messenger RNA maturation. To date, only two hypomorphic variants have been identified. We report on a cohort of 26 patients affected with TAR syndrome and carrying biallelic variants in RBM8A. Half patients carried a 1q21.1 deletion and one of the two known hypomorphic variants. Four novel noncoding variants of RBM8A were identified in the remaining patients. We developed experimental models enabling their functional characterization in vitro. Two variants, located respectively in the 5'-untranslated region (5'-UTR) and 3'-UTR regions, are responsible for a diminished expression whereas two intronic variants alter splicing. Our results bring new insights into the molecular knowledge of TAR syndrome and enabled us to propose genetic counseling for patients' families.
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http://dx.doi.org/10.1002/humu.24021DOI Listing
July 2020

Homozygous Loss-of-Function Mutations in CCDC134 Are Responsible for a Severe Form of Osteogenesis Imperfecta.

J Bone Miner Res 2020 08 14;35(8):1470-1480. Epub 2020 Apr 14.

Department of Clinical Genetics and Reference Centre for Constitutional Bone Diseases, INSERM U1163, Université de Paris, Imagine Institute, Necker-Enfants Malades Hospital, AP-HP, F-75015, Paris, France.

Osteogenesis imperfecta (OI) is a primary bone fragility disorder with an estimated prevalence of 1 in 15,000 births. The majority of OI cases are inherited in an autosomal-dominant manner, while 5% to 10% have recessive or X-linked inheritance. Up to now, approximately 5% of OI cases remain without mutation demonstrated, supporting the involvement of other genes in the disease spectrum. By whole-exome sequencing, we identified a homozygous variant (c.2T>C) in CCDC134 gene in three patients from two unrelated families with severe bone fragility that did not respond to bisphosphonate treatment, short stature, and gracile long bones with pseudarthroses but no dentinogenesis imperfecta. CCDC134 encodes a secreted protein widely expressed and implicated in the regulation of some mitogen-activated protein kinases (MAPK) signaling pathway. Western blot and immunofluorescence analyses confirmed the absence of CCDC134 protein in patient cells compared with controls. Furthermore, we demonstrated that CCDC134 mutations are associated with increased Erk1/2 phosphorylation, decreased OPN mRNA and COL1A1 expression and reduced mineralization in patient osteoblasts compared with controls. These data support that CCDC134 is a new gene involved in severe progressive deforming recessive osteogenesis imperfecta (type III). © 2020 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.4011DOI Listing
August 2020

Growth charts in Kabuki syndrome 1.

Am J Med Genet A 2020 03 26;182(3):446-453. Epub 2019 Dec 26.

Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Univer Montpellier, CHU de Montpellier, CLAD ASOOR Montpellier, France.

Kabuki syndrome (KS, KS1: OMIM 147920 and KS2: OMIM 300867) is caused by pathogenic variations in KMT2D or KDM6A. KS is characterized by multiple congenital anomalies and neurodevelopmental disorders. Growth restriction is frequently reported. Here we aimed to create specific growth charts for individuals with KS1, identify parameters used for size prognosis and investigate the impact of growth hormone therapy on adult height. Growth parameters and parental size were obtained for 95 KS1 individuals (41 females). Growth charts for height, weight, body mass index (BMI) and occipitofrontal circumference were generated in standard deviation values for the first time in KS1. Statural growth of KS1 individuals was compared to parental target size. According to the charts, height, weight, BMI, and occipitofrontal circumference were lower for KS1 individuals than the normative French population. For males and females, the mean growth of KS1 individuals was -2 and -1.8 SD of their parental target size, respectively. Growth hormone therapy did not increase size beyond the predicted size. This study, from the largest cohort available, proposes growth charts for widespread use in the management of KS1, especially for size prognosis and screening of other diseases responsible for growth impairment beyond a calculated specific target size.
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http://dx.doi.org/10.1002/ajmg.a.61462DOI Listing
March 2020

A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.

Eur J Med Genet 2020 Apr 7;63(4):103823. Epub 2019 Dec 7.

Centre de Génétique Humaine, Centre Hospitalier Régional Universitaire, Université de Franche-Comté, Besançon, France; Unité de recherche en neurosciences intégratives et cognitives EA481, Université de Franche-Comté, Besançon, France. Electronic address:

A narrow thorax with shortening of long bones is usually pointing to dysfunction of the primary cilia corresponding clinically to ciliopathies with major skeletal involvement. Mutations in at least 23 genes are likely to correspond to this clinical presentation: IFT43/52/80/81/122/140/172, WDR19/34/35/60, DYNC2H1, DYNC2LI1, CEP120, NEK1, TTC21B, TCTEX1D2, INTU, TCTN3, EVC 1/2 and KIAA0586. In addition to these, KIAA0753 variants were recently described in seven patients with Jeune asphyxiating thoracic dystrophy (ATD) (two first cousins, one unrelated patient and one fetus), Joubert syndrome (two siblings) and orofaciodigital syndrome type 6 (one patient). We present the clinical characteristics of a eighth such patient. This 4 year-old boy with narrow thorax, short limbs, severe respiratory and feeding difficulties from birth on had a history of hypotonia and developmental delay. On skeletal survey, short tubular bones (height - 5,5 SD) and a trident appearance of the pelvis were seen. Brain MRI showed cervical canal stenosis. Renal function was normal and moderate hepatomegaly was noted. A homozygous c.943C > T mutation in KIAA0753 was identified on whole exome sequencing, resulting in Gln315Ter premature termination of the corresponding protein. This case provides confirmation of an additional molecular basis for skeletal dysplasia and illustrates how ciliopathies due to mutations in a single gene may present as apparently distinct syndromes.
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http://dx.doi.org/10.1016/j.ejmg.2019.103823DOI Listing
April 2020

Sleep-disordered breathing in children with pycnodysostosis.

Am J Med Genet A 2020 01 3;182(1):122-129. Epub 2019 Nov 3.

ASV Santé, Gennevilliers, France.

Upper airway obstruction is a common feature in pycnodysostosis and may cause obstructive sleep apnea (OSA). The aim of our study was to analyze sleep-disordered breathing and respiratory management in children with pycnodysostosis. A retrospective review of the clinical charts and sleep studies of 10 consecutive children (three girls and seven boys) with pycnodysostosis seen over a time period of 10 years was performed. Six patients had severe OSA and/or nocturnal hypoventilation and were started on continuous positive airway pressure (CPAP) as a first treatment at a median age of 3.4 ± 2.6 years, because of the lack of indication of any surgical treatment. Three patients could be weaned after several years from CPAP after spontaneous improvement (two patients) or multiple upper airway surgeries (one patient). Three patients had upper airway surgery prior to their first sleep study with two patients still needing CPAP during their follow-up. Only one patient never developed OSA. Patients with pycnodysostosis are at a high risk of severe OSA, underlying the importance of a systematic screening for sleep-disordered breathing. Multidisciplinary care is mandatory because of the multilevel airway obstruction. CPAP is very effective and well accepted for treating OSA.
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http://dx.doi.org/10.1002/ajmg.a.61393DOI Listing
January 2020

Expanding the phenotype in Adams-Oliver syndrome correlating with the genotype.

Am J Med Genet A 2020 01 25;182(1):29-37. Epub 2019 Oct 25.

AP-HP, Service de Génétique Clinique, Necker-Enfants malades University Hospital, Paris, France.

Rationale: Adams-Oliver syndrome (AOS) is a genetic disorder characterized by the association of aplasia cutis congenita (ACC), terminal transverse limb defect (TTLD), congenital cardiac malformation (CCM), and minor features, such as cutaneous, neurological, and hepatic abnormalities (HAs). The aim of the study is to emphasize phenotype-genotype correlations in AOS.

Methods: We studied 29 AOS patients. We recorded retrospectively detailed phenotype data, including clinical examination, biological analyses, and imaging. The molecular analysis was performed through whole exome sequencing (WES).

Results: Twenty-nine patients (100%) presented with ACC, the principal inclusion criteria in the study. Seventeen of twenty-one (81%) had cutis marmorata telangiectasia congenita, 16/26 (62%) had TTLD, 14/23 (61%) had CCM, 7/20 (35%) had HAs, and 9/27 (33%) had neurological findings. WES was performed in 25 patients. Fourteen of twenty-five (56%) had alterations in the genes already described in AOS. CCM and HAs are particularly associated with the NOTCH1 genotype. TTLD is present in patients with DOCK6 and EOGT alterations. Neurological findings of variable degree were associated sometimes with DOCK6 and NOTCH1 rarely with EOGT.

Conclusion: AOS is characterized by a clinical and molecular variability. It appears that degrees of genotype-phenotype correlations exist for patients with identified pathogenic mutations, underlining the need to undertake a systematic but adjusted multidisciplinary assessment.
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http://dx.doi.org/10.1002/ajmg.a.61364DOI Listing
January 2020

PAPSS2-related brachyolmia: Clinical and radiological phenotype in 18 new cases.

Am J Med Genet A 2019 09 16;179(9):1884-1894. Epub 2019 Jul 16.

Clinical Genetics, St Michael's Hospital Bristol, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.

Brachyolmia is a skeletal dysplasia characterized by short spine-short stature, platyspondyly, and minor long bone abnormalities. We describe 18 patients, from different ethnic backgrounds and ages ranging from infancy to 19 years, with the autosomal recessive form, associated with PAPSS2. The main clinical features include disproportionate short stature with short spine associated with variable symptoms of pain, stiffness, and spinal deformity. Eight patients presented prenatally with short femora, whereas later in childhood their short-spine phenotype emerged. We observed the same pattern of changing skeletal proportion in other patients. The radiological findings included platyspondyly, irregular end plates of the elongated vertebral bodies, narrow disc spaces and short over-faced pedicles. In the limbs, there was mild shortening of femoral necks and tibiae in some patients, whereas others had minor epiphyseal or metaphyseal changes. In all patients, exome and Sanger sequencing identified homozygous or compound heterozygous PAPSS2 variants, including c.809G>A, common to white European patients. Bi-parental inheritance was established where possible. Low serum DHEAS, but not overt androgen excess was identified. Our study indicates that autosomal recessive brachyolmia occurs across continents and may be under-recognized in infancy. This condition should be considered in the differential diagnosis of short femora presenting in the second trimester.
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http://dx.doi.org/10.1002/ajmg.a.61282DOI Listing
September 2019

Pycnodysostosis: Natural history and management guidelines from 27 French cases and a literature review.

Clin Genet 2019 10 25;96(4):309-316. Epub 2019 Jun 25.

Department of Medical Genetics, Reference Center for Skeletal Dysplasia and OSCAR Network, Paris Descartes-Sorbonne Paris Cité University, INSERM UMR 1163, Instititut Imagine, Hôpital Necker Enfants Malades, Paris, France.

Pycnodysostosis is a lysosomal autosomal recessive skeletal dysplasia characterized by osteosclerosis, short stature, acro-osteolysis, facial features and an increased risk of fractures. The clinical heterogeneity of the disease and its rarity make it difficult to provide patients an accurate prognosis, as well as appropriate care and follow-up. French physicians from the OSCAR network have been asked to fill out questionnaires collecting molecular and clinical data for 27 patients issued from 17 unrelated families. All patients showed short stature (mean = -3.5 SD) which was more severe in females (P = .006). The mean fracture rate was moderate (0.21 per year), with four fractures in total average. About 75% underwent at least one surgery, with an average number of 2.1 interventions per patient. About 50% required non-invasive assisted ventilation due to sleep apnea (67%). About 29% showed psychomotor difficulties and 33% needed a school assistant or adapted schooling. No patient had any psychological evaluation or follow-up. Molecular data were available for 14 families. Growth hormone administration was efficient on linear growth in 40% of cases. We propose several axis of management, such as systematic cerebral MRI for Chiari malformation screening at diagnosis and regular psychological follow-up.
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http://dx.doi.org/10.1111/cge.13591DOI Listing
October 2019

Sleep-disordered breathing in children with mucolipidosis.

Am J Med Genet A 2019 07 30;179(7):1196-1204. Epub 2019 Apr 30.

AP-HP, Hôpital Necker Enfants-Malades, Pediatric Noninvasive Ventilation and Sleep Unit, Paris, France.

Mucolipidosis (ML) is a rare lysosomal storage disorder with a wide spectrum of disease severity according to the type. Sleep-disordered breathing is recognized as a characteristic feature of ML but objective data are scarce. The aim of the study was to describe sleep data and medical management in children with ML α/β. All patients with ML α/β followed at a national reference center of ML were included. Five patients had ML II, one patient had ML III and one patient had ML II-III. One patient was started on noninvasive ventilation (NIV) to allow extubation after prolonged invasive mechanical ventilation. The six other patients underwent sleep study at a median age of 1.8 years (range 4 months-17.4 years). Obstructive sleep apnea (OSA) was observed in all patients with a median apnea-hypopnea index (AHI) of 36 events/hr (range 5-52) requiring continuous positive airway pressure (CPAP) or NIV. CPAP/NIV resulted in an improvement of nocturnal gas exchange and was continued in all patients with an excellent compliance. Two patients died. Systematic sleep studies are recommended at time of diagnosis in ML. CPAP or NIV are effective treatments of OSA, well tolerated, and may contribute to improve the quality of life of patients and caregivers.
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http://dx.doi.org/10.1002/ajmg.a.61167DOI Listing
July 2019

Intermediate autosomal recessive osteopetrosis with a large noncoding deletion in SNX10: A case report.

Pediatr Blood Cancer 2019 07 12;66(7):e27751. Epub 2019 Apr 12.

UF de Génétique Moléculaire, Service de Biochimie et Biologie Moléculaire, Hôpital Lariboisière, Paris, France.

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http://dx.doi.org/10.1002/pbc.27751DOI Listing
July 2019

Delineating syndrome: From congenital microcephaly to hyperkinetic encephalopathy.

Neurol Genet 2018 Dec 7;4(6):e281. Epub 2018 Nov 7.

Objective: To provide new insights into the related clinical and imaging phenotypes and refine the phenotype-genotype correlation in syndrome.

Methods: We analyzed the clinical and imaging phenotypes of a cohort of 45 patients with a pathogenic or likely pathogenic variant and performed phenotype-genotype correlations.

Results: A total of 37 different heterozygous mutations were identified, of which 18 are novel. We described a broad spectrum of neurodevelopmental phenotypes, characterized by severe postnatal microcephaly and developmental delay accompanied by a hyperkinetic movement disorder, stereotypes and sleep disorders, and epileptic seizures. Our data highlighted 3 patterns of gyration, including frontal pachygyria in younger patients (26.7%), moderate simplified gyration (24.4%) and mildly simplified or normal gyration (48.9%), corpus callosum hypogenesis mostly in its frontal part, combined with moderate-to-severe myelination delay that improved and normalized with age. Frameshift and nonsense mutations in the N-terminus of , which are the most common mutation types, show the most severe clinical features and MRI anomalies. However, patients with recurrent frameshift mutations c.460dupG and c.256dupC had variable clinical and imaging presentations.

Conclusions: These findings have implications for genetic counseling, providing evidence that N-terminal mutations and large deletions lead to more severe syndrome, although genotype-phenotype correlations are not necessarily straightforward in recurrent mutations. Together, these analyses support the view that syndrome is a specific disorder characterized by frontal pachygyria and delayed myelination in its most severe form and hypogenetic corpus callosum in its milder form.
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http://dx.doi.org/10.1212/NXG.0000000000000281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244024PMC
December 2018

A retrospective study on sleep-disordered breathing in Morquio-A syndrome.

Am J Med Genet A 2018 12 18;176(12):2595-2603. Epub 2018 Nov 18.

Pediatric Noninvasive Ventilation and Sleep Unit, AP-HP, Hôpital Necker-Enfants Malades, Paris, France.

Respiratory problems are common in Morquio-A syndrome (MPS IVA) but objective data on sleep-disordered breathing are scarce. The aim of our study was to review polygraphic (PG) findings and the need for noninvasive continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV) in children with MPS IVA. A retrospective review of the clinical charts and PG of 16 consecutive children (7 boys, mean age 10.5 ± 4.2 years) with MPS IVA seen over a period of 3 years was performed. The prevalence of obstructive sleep apnea (OSA) was 69% with only five patients, all younger than 10 years old, having a normal PG. Four patients had mild OSA (apnea-hypopnea index [AHI] ≥1.5 and <5 events/hr), three patients had moderate OSA (AHI ≥5 and <10 events/hr), and three patients had severe OSA (AHI ≥ 10 events/hr). Among the 10 patients with OSA, 3 had prior adenoidectomy ± tonsillectomy and 6 were on enzyme replacement therapy. Only one patient had a central apnea index >5 events/hr despite prior cervico-occipital decompression. Six patients, all older than 11 years old, were started on CPAP or NIV because of severe OSA (n = 4), nocturnal hypoventilation (n = 1), or impossibility to be weaned from NIV after an acute respiratory failure (n = 1). Prevalence of OSA is high in patients with MPS IVA, underlying the importance of a systematic screening for sleep-disordered breathing. CPAP and NIV are efficient and well accepted for treating sleep-disordered breathing.
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http://dx.doi.org/10.1002/ajmg.a.40642DOI Listing
December 2018

Expanding the phenotypic spectrum of variants in PDE4D/PRKAR1A: from acrodysostosis to acroscyphodysplasia.

Eur J Hum Genet 2018 11 13;26(11):1611-1622. Epub 2018 Jul 13.

Department of Medical Genetics, INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, IMAGINE Institute, Necker Enfants Malades Hospital, Paris, France.

Acrodysostosis (MIM 101800) is a dominantly inherited condition associating (1) skeletal features (short stature, facial dysostosis, and brachydactyly with cone-shaped epiphyses), (2) resistance to hormones and (3) possible intellectual disability. Acroscyphodysplasia (MIM 250215) is characterized by growth retardation, brachydactyly, and knee epiphyses embedded in cup-shaped metaphyses. We and others have identified PDE4D or PRKAR1A variants in acrodysostosis; PDE4D variants have been reported in three cases of acroscyphodysplasia. Our study aimed at reviewing the clinical and molecular findings in a cohort of 27 acrodysostosis and 5 acroscyphodysplasia cases. Among the acrodysostosis cases, we identified 9 heterozygous de novo PRKAR1A variants and 11 heterozygous PDE4D variants. The 7 patients without variants presented with symptoms of acrodysostosis (brachydactyly and cone-shaped epiphyses), but none had the characteristic facial dysostosis. In the acroscyphodysplasia cases, we identified 2 PDE4D variants. For 2 of the 3 negative cases, medical records revealed early severe infection, which has been described in some reports of acroscyphodysplasia. Subdividing our series of acrodysostosis based on the disease-causing gene, we confirmed genotype-phenotype correlations. Hormone resistance was consistently observed in patients carrying PRKAR1A variants, whereas no hormone resistance was observed in 9 patients with PDE4D variants. All patients with PDE4D variants shared characteristic facial features (midface hypoplasia with nasal hypoplasia) and some degree of intellectual disability. Our findings of PDE4D variants in two cases of acroscyphodysplasia support that PDE4D may be responsible for this severe skeletal dysplasia. We eventually emphasize the importance of some specific assessments in the long-term follow up, including cardiovascular and thromboembolic risk factors.
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http://dx.doi.org/10.1038/s41431-018-0135-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189044PMC
November 2018

Targeted therapy in patients with PIK3CA-related overgrowth syndrome.

Nature 2018 06 13;558(7711):540-546. Epub 2018 Jun 13.

INSERM U1151, Institut Necker Enfants Malades, Paris, France.

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.
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http://dx.doi.org/10.1038/s41586-018-0217-9DOI Listing
June 2018

Identification of PITX3 mutations in individuals with various ocular developmental defects.

Ophthalmic Genet 2018 06 6;39(3):314-320. Epub 2018 Feb 6.

a UDEAR , Université de Toulouse, UMRS 1056 INSERM-Université Paul Sabatier , Toulouse , France.

Background: Congenital cataract displays large phenotypic (syndromic and isolated cataracts) and genetic heterogeneity. Mutations in several transcription factors involved in eye development, like PITX3, have been associated with congenital cataracts and anterior segment mesenchymal disorders.

Materials And Methods: Targeted sequencing of 187 genes involved in ocular development was performed in 96 patients with mainly anophthalmia and microphthalmia. Additionally, Sanger sequencing analysis of PITX3 was performed on a second cohort of 32 index cases with congenital cataract and Peters anomaly and/or sclereocornea.

Results: We described five families with four different PITX3 mutations, two of which were novel. In Family 1, the heterozygous recurrent c.640_656dup (p.Gly220Profs*95) mutation cosegregated with eye anomalies ranging from congenital cataract to Peters anomaly. In Family 2, the novel c.669del [p.(Leu225Trpfs*84)] mutation cosegregated with dominantly inherited eye anomalies ranging from posterior embryotoxon to congenital cataract in heterozygous carriers and congenital sclereocornea and cataract in a patient homozygous for this mutation. In Family 3, we identified the recurrent heterozygous c.640_656dup (p.Gly220Profs*95) mutation segregating with congenital cataract. In Family 4, the de novo c.582del [p.(Ile194Metfs*115)] mutation was identified in a patient with congenital cataract, microphthalmia, developmental delay and autism. In Family 5, the c.38G>A (p.Ser13Asn) mutation segregated dominantly in a family with Peters anomaly, which is a novel phenotype associated with the c.38G>A variant compared with the previously reported isolated congenital cataract.

Conclusions: Our study unveils different phenotypes associated with known and novel mutations in PITX3, which will improve the genetic counselling of patients and their families.
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http://dx.doi.org/10.1080/13816810.2018.1430243DOI Listing
June 2018

mutations are responsible for autosomal recessive osteogenesis imperfecta.

J Med Genet 2018 04 22;55(4):278-284. Epub 2018 Jan 22.

Department of Medical Genetics, INSERM U1163, Université Paris-Descartes, Institut Imagine, Hôpital Necker-Enfants Malades, Paris, France.

Background: Stüve-Wiedemann syndrome (SWS) is characterised by bowing of the lower limbs, respiratory distress and hyperthermia that are often responsible for early death. Survivors develop progressive scoliosis and spontaneous fractures. We previously identified mutations in most SWS cases, but absence of pathogenic changes in five patients led us to perform exome sequencing and to identify homozygosity for a mutation in one case [p.Ser205Tyrfs*13]. The follow-up of this case supported a final diagnosis of osteogenesis imperfecta (OI), based on vertebral collapses and blue sclerae.

Methods And Results: This prompted us to screen in 25 OI patients with no known mutations.We identified a homozygous deleterious variant in in two affected sibs with typical OI [p.His127Arg]. Another homozygous variant, [p.Asp231Gly], also classed as deleterious, was detected in a patient with type III OI of consanguineous parents using homozygosity mapping and exome sequencing.FAM46A is a member of the superfamily of nucleotidyltransferase fold proteins but its exact function is presently unknown. Nevertheless, there are lines of evidence pointing to a relevant role of FAM46A in bone development. By RT-PCR analysis, we detected specific expression of in human osteoblasts andinterestingly, a nonsense mutation in has been recently identified in an ENU-derived (-ethyl--nitrosourea) mouse model characterised by decreased body length, limb, rib, pelvis, and skull deformities and reduced cortical thickness in long bones.

Conclusion: We conclude that mutations are responsible for a severe form of OI with congenital bowing of the lower limbs and suggest screening this gene in unexplained OI forms.
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http://dx.doi.org/10.1136/jmedgenet-2017-104999DOI Listing
April 2018

Whole exome sequencing diagnoses the first fetal case of Bainbridge-Ropers syndrome presenting as pontocerebellar hypoplasia type 1.

Birth Defects Res 2018 04 8;110(6):538-542. Epub 2018 Jan 8.

Unité d'Embryofœtopathologie, Service d'Histologie Embryologie Cytogénétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (APHP), Paris, France.

Background: Bainbridge-Ropers syndrome (BRPS) is a recently identified severe disorder characterized by failure to thrive, facial dysmorphism, and severe developmental delay, caused by de novo dominant loss of function mutation in the ASXL3 gene.

Case: We report here the first case of prenatal BRPS in a fetus presenting with arthrogryposis on ultrasound and for pontocerebellar hypoplasia type 1 (PCH1) following neuropathological examination. The diagnosis was done by whole exome sequencing that identified a novel de novo ASXL3 mutation. We review 29 previous published cases.

Discussion: The fetopathological examination allowed to extend the phenotype to central nervous system and the genetic study highlights ASXL3 as a dominant gene responsible for PCH1 phenotype. Recognizing heterozygous ASXL3 mutation as a cause of prenatal PCH1 is essential for both large scale molecular analysis in the NGS era and genetic counseling.
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http://dx.doi.org/10.1002/bdr2.1191DOI Listing
April 2018

Chromosomal rearrangements in the 11p15 imprinted region: 17 new 11p15.5 duplications with associated phenotypes and putative functional consequences.

J Med Genet 2018 03 9;55(3):205-213. Epub 2017 Dec 9.

AP-HP, Hôpitaux Universitaires Paris Est, Hôpital des Enfants Armand Trousseau, Service d'Explorations Fonctionnelles Endocriniennes, Paris, France.

Background: The 11p15 region contains two clusters of imprinted genes. Opposite genetic and epigenetic anomalies of this region result in two distinct growth disturbance syndromes: Beckwith-Wiedemann (BWS) and Silver-Russell syndromes (SRS). Cytogenetic rearrangements within this region represent less than 3% of SRS and BWS cases. Among these, 11p15 duplications were infrequently reported and interpretation of their pathogenic effects is complex.

Objectives: To report cytogenetic and methylation analyses in a cohort of patients with SRS/BWS carrying 11p15 duplications and establish genotype/phenotype correlations.

Methods: From a cohort of patients with SRS/BWS with an abnormal methylation profile (using ASMM-RTQ-PCR), we used SNP-arrays to identify and map the 11p15 duplications. We report 19 new patients with SRS (n=9) and BWS (n=10) carrying de novo or familial 11p15 duplications, which completely or partially span either both telomeric and centromeric domains or only one domain.

Results: Large duplications involving one complete domain or both domains are associated with either SRS or BWS, depending on the parental origin of the duplication. Genotype-phenotype correlation studies of partial duplications within the telomeric domain demonstrate the prominent role of , rather than , in the control of growth. Furthermore, it highlights the role of within the centromeric domain and suggests that the expected overexpression of from the paternal allele (in partial paternal duplications, excluding ) does not affect the expression of .

Conclusions: The phenotype associated with 11p15 duplications depends on the size, genetic content, parental inheritance and imprinting status. Identification of these rare duplications is crucial for genetic counselling.
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http://dx.doi.org/10.1136/jmedgenet-2017-104919DOI Listing
March 2018

Prevalence of fibrodysplasia ossificans progressiva (FOP) in France: an estimate based on a record linkage of two national databases.

Orphanet J Rare Dis 2017 06 30;12(1):123. Epub 2017 Jun 30.

Institut Imagine, Centre de Référence Maladies Osseuses Constitutionnelles, Université Paris Descartes-Sorbonne Paris Cité, Hôpital Necker-Enfants malades, 149 rue de Sèvres, 75015, Paris, France.

Background: Fibrodysplasia ossificans progressiva (FOP) is a rare, severely disabling, and life-shortening genetic disorder that causes the formation of heterotopic bone within soft connective tissue. Previous studies found that the FOP prevalence was about one in every two million lives. The aim of this study is to estimate the FOP prevalence in France by probabilistic record-linkage of 2 national databases: 1) the PMSI (Programme de médicalisation des systèmes d'information), an administrative database that records all hospitalization activities in France and 2) CEMARA, a registry database developed by the French Centres of Reference for Rare Diseases.

Results: Using a capture-recapture methodology to adjust the crude number of patients identified in both data sources, 89 FOP patients were identified, which results in a prevalence of 1.36 per million inhabitants (CI95% = [1.10; 1.68]). FOP patients' mean age was 25 years, only 14.9% were above 40 years, and 53% of them were males. The first symptoms - beside toe malformations- occurred after birth for 97.3% of them. Mean age at identified symptoms was 7 years and above 18 years for only 6.9% of patients. Mean age at diagnosis was 10 years, and above 18 years for 14.9% of the patients. FOP patients were distributed across France.

Conclusions: Despite the challenge of ascertaining patients with rare diseases, we report a much higher prevalence of FOP in France than in previous studies elsewhere. We suggest that efforts to identify patients and confirm the diagnosis of FOP should be reinforced and extended at both national and European level.
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http://dx.doi.org/10.1186/s13023-017-0674-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493013PMC
June 2017

Phenotypes and genotypes in individuals with SMC1A variants.

Am J Med Genet A 2017 Aug 26;173(8):2108-2125. Epub 2017 May 26.

Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.
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http://dx.doi.org/10.1002/ajmg.a.38279DOI Listing
August 2017

Sleep-disordered breathing and its management in children with achondroplasia.

Am J Med Genet A 2017 Apr 27;173(4):868-878. Epub 2017 Feb 27.

AP-HP, Hôpital Necker-Enfants malades, Pediatric Noninvasive Ventilation and Sleep Unit, Paris, France.

Sleep-disordered breathing is a common feature in children with achondroplasia. The aim of our study was to review the poly(somno)graphic (P(S)G) findings and consequent treatments in children with achondroplasia followed in the national reference center for skeletal dysplasia. A retrospective review of the clinical charts and P(S)G of 43 consecutive children (mean age 3.9 ± 3.5 years) with achondroplasia seen over a period of 2 years was performed. Twenty four (59%) children had obstructive sleep apnea (OSA). Thirteen children had an obstructive apnea-hypopnea index (OAHI) < 5/hr, four had an OAHI between 5 and 10/hr, and seven had an OAHI ≥ 10/hr. Ten of the 15 children who had previous upper airway surgery still had an abnormal P(S)G. All the patients with an AHI ≥ 10/hr were under 7 years of age and none had a prior tonsillectomy. The children who underwent adeno-tonsillectomy, coupled in most cases with turbinectomy, were significantly older (mean age 7.5 ± 3.5 vs. 3.5 ± 1.7 years old, P = 0.015) and had significantly better P(S)G results than those who underwent only adeno-turbinectomy. No correlation was observed between the mean AHI value at the baseline P(S)G and the type of academic course (standard, supported or specialized). In conclusion, OSA is common in children with achondroplasia. The observation of a reduced prevalence of OSA after (adeno-)tonsillectomy is in favor of this type of surgery when possible.
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http://dx.doi.org/10.1002/ajmg.a.38130DOI Listing
April 2017

Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing.

Genet Med 2017 09 2;19(9):989-997. Epub 2017 Feb 2.

Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement, CHU Dijon Bourgogne, Dijon, France.

Purpose: Postzygotic activating mutations of PIK3CA cause a wide range of mosaic disorders collectively referred to as PIK3CA-related overgrowth spectrum (PROS). We describe the diagnostic yield and characteristics of PIK3CA sequencing in PROS.

Methods: We performed ultradeep next-generation sequencing (NGS) of PIK3CA in various tissues from 162 patients referred to our clinical laboratory and assessed diagnostic yield by phenotype and tissue tested.

Results: We identified disease-causing mutations in 66.7% (108/162) of patients, with mutant allele levels as low as 1%. The diagnostic rate was higher (74%) in syndromic than in isolated cases (35.5%; P = 9.03 × 10). We identified 40 different mutations and found strong oncogenic mutations more frequently in patients without brain overgrowth (50.6%) than in those with brain overgrowth (15.2%; P = 0.00055). Mutant allele levels were higher in skin and overgrown tissues than in blood and buccal samples (P = 3.9 × 10), regardless of the phenotype.

Conclusion: Our data demonstrate the value of ultradeep NGS for molecular diagnosis of PROS, highlight its substantial allelic heterogeneity, and confirm that optimal diagnosis requires fresh skin or surgical samples from affected regions. Our findings may be of value in guiding future recommendations for genetic testing in PROS and other mosaic conditions.Genet Med advance online publication 02 February 2017.
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http://dx.doi.org/10.1038/gim.2016.220DOI Listing
September 2017

Gain-of-function mutations in SMAD4 cause a distinctive repertoire of cardiovascular phenotypes in patients with Myhre syndrome.

Am J Med Genet A 2016 10 14;170(10):2617-31. Epub 2016 Jun 14.

Thoracic Aortic Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Myhre syndrome is a rare, distinctive syndrome due to specific gain-of-function mutations in SMAD4. The characteristic phenotype includes short stature, dysmorphic facial features, hearing loss, laryngotracheal anomalies, arthropathy, radiographic defects, intellectual disability, and a more recently appreciated spectrum of cardiovascular defects with a striking fibroproliferative response to surgical intervention. We report four newly described patients with typical features of Myhre syndrome who had (i) a mildly narrow descending aorta and restrictive cardiomyopathy; (ii) recurrent pericardial and pleural effusions; (iii) a large persistent ductus arteriosus with juxtaductal aortic coarctation; and (iv) restrictive pericardial disease requiring pericardiectomy. Additional information is provided about a fifth previously reported patient with fatal pericardial disease. A literature review of the cardiovascular features of Myhre syndrome was performed on 54 total patients, all with a SMAD4 mutation. Seventy percent had a cardiovascular abnormality including congenital heart defects (63%), pericardial disease (17%), restrictive cardiomyopathy (9%), and systemic hypertension (15%). Pericarditis and restrictive cardiomyopathy are associated with high mortality (three patients each among 10 deaths); one patient with restrictive cardiomyopathy also had epicarditis. Cardiomyopathy and pericardial abnormalities distinguish Myhre syndrome from other disorders caused by mutations in the TGF-β signaling cascade (Marfan, Loeys-Dietz, or Shprintzen-Goldberg syndromes). We hypothesize that the expanded spectrum of cardiovascular abnormalities relates to the ability of the SMAD4 protein to integrate diverse signaling pathways, including canonical TGF-β, BMP, and Activin signaling. The co-occurrence of congenital and acquired phenotypes demonstrates that the gene product of SMAD4 is required for both developmental and postnatal cardiovascular homeostasis. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37739DOI Listing
October 2016

Uncommon nucleotide excision repair phenotypes revealed by targeted high-throughput sequencing.

Orphanet J Rare Dis 2016 Mar 22;11:26. Epub 2016 Mar 22.

Laboratoire de Génétique Médicale - INSERM U1112, Institut de Génétique Médicale d'Alsace (IGMA), Faculté de médecine de Strasbourg, 11 rue Humann, Strasbourg, France.

Background: Deficient nucleotide excision repair (NER) activity causes a variety of autosomal recessive diseases including xeroderma pigmentosum (XP) a disorder which pre-disposes to skin cancer, and the severe multisystem condition known as Cockayne syndrome (CS). In view of the clinical overlap between NER-related disorders, as well as the existence of multiple phenotypes and the numerous genes involved, we developed a new diagnostic approach based on the enrichment of 16 NER-related genes by multiplex amplification coupled with next-generation sequencing (NGS).

Methods: Our test cohort consisted of 11 DNA samples, all with known mutations and/or non pathogenic SNPs in two of the tested genes. We then used the same technique to analyse samples from a prospective cohort of 40 patients. Multiplex amplification and sequencing were performed using AmpliSeq protocol on the Ion Torrent PGM (Life Technologies).

Results: We identified causative mutations in 17 out of the 40 patients (43%). Four patients showed biallelic mutations in the ERCC6(CSB) gene, five in the ERCC8(CSA) gene: most of them had classical CS features but some had very mild and incomplete phenotypes. A small cohort of 4 unrelated classic XP patients from the Basque country (Northern Spain) revealed a common splicing mutation in POLH (XP-variant), demonstrating a new founder effect in this population. Interestingly, our results also found ERCC2(XPD), ERCC3(XPB) or ERCC5(XPG) mutations in two cases of UV-sensitive syndrome and in two cases with mixed XP/CS phenotypes.

Conclusions: Our study confirms that NGS is an efficient technique for the analysis of NER-related disorders on a molecular level. It is particularly useful for phenotypes with combined features or unusually mild symptoms. Targeted NGS used in conjunction with DNA repair functional tests and precise clinical evaluation permits rapid and cost-effective diagnosis in patients with NER-defects.
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http://dx.doi.org/10.1186/s13023-016-0408-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804614PMC
March 2016

RPL10 mutation segregating in a family with X-linked syndromic Intellectual Disability.

Am J Med Genet A 2015 Aug 6;167A(8):1908-12. Epub 2015 Apr 6.

Service de Génétique, INSERM U781, Hôpital Necker-Enfants Malades, Institut Imagine, University Sorbonne-Paris-Cité, Paris, France.

Intellectual disability is a neurodevelopmental disorder of impaired adaptive skills and low intelligence quotient. The overall prevalence is estimated at 2-3% in the general population with extreme clinical and genetic heterogeneity, and it has been associated with possibly causative mutations in more than 700 identified genes. In a recent review, among over 100 X-linked intellectual disability causative genes, eight were reported as "awaiting replication." Exome sequencing in a large family identified a missense mutation in RPL10 highly suggestive of X-linked intellectual disability. Herein, we report on the clinical description of four affected males. All patients presented apparent intellectual disability (4/4), psychomotor delay (4/4) with syndromic features including amniotic fluid excess (3/4), microcephaly (2/4), urogenital anomalies (3/4), cerebellar syndrome (2/4), and facial dysmorphism. In the literature, two mutations were reported in three families with affected males presenting with autism. This report confirms the implication of RPL10 mutations in neurodevelopmental disorders and extends the associated clinical spectrum from autism to syndromic intellectual disability.
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http://dx.doi.org/10.1002/ajmg.a.37094DOI Listing
August 2015

Extensive investigation of the IGF2/H19 imprinting control region reveals novel OCT4/SOX2 binding site defects associated with specific methylation patterns in Beckwith-Wiedemann syndrome.

Hum Mol Genet 2014 Nov 10;23(21):5763-73. Epub 2014 Jun 10.

INSERM, UMR_S 938, CDR Saint-Antoine, Paris F-75012, France, Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris F-75012, France, Pediatric Endocrinology, APHP, Armand Trousseau Hospital, Paris, France,

Isolated gain of methylation (GOM) at the IGF2/H19 imprinting control region 1 (ICR1) accounts for about 10% of patients with BWS. A subset of these patients have genetic defects within ICR1, but the frequency of these defects has not yet been established in a large cohort of BWS patients with isolated ICR1 GOM. Here, we carried out a genetic analysis in a large cohort of 57 BWS patients with isolated ICR1 GOM and analyzed the methylation status of the entire domain. We found a new point mutation in two unrelated families and a 21 bp deletion in another unrelated child, both of which were maternally inherited and affected the OCT4/SOX2 binding site in the A2 repeat of ICR1. Based on data from this and previous studies, we estimate that cis genetic defects account for about 20% of BWS patients with isolated ICR1 GOM. Methylation analysis at eight loci of the IGF2/H19 domain revealed that sites surrounding OCT4/SOX2 binding site mutations were fully methylated and methylation indexes declined as a function of distance from these sites. This was not the case in BWS patients without genetic defects identified. Thus, GOM does not spread uniformly across the IGF2/H19 domain, suggesting that OCT4/SOX2 protects against methylation at local sites. These findings add new insights to the mechanism of the regulation of the ICR1 domain. Our data show that mutations and deletions within ICR1 are relatively common. Systematic identification is therefore necessary to establish appropriate genetic counseling for BWS patients with isolated ICR1 GOM.
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http://dx.doi.org/10.1093/hmg/ddu290DOI Listing
November 2014

Myhre and LAPS syndromes: clinical and molecular review of 32 patients.

Eur J Hum Genet 2014 Nov 15;22(11):1272-7. Epub 2014 Jan 15.

INSERM U781 Unit, Department of Genetics, Institut Imagine, Paris Descartes University-Sorbonne Paris Cité, Necker Enfants-Malades Hospital, Paris, France.

Myhre syndrome is characterized by short stature, brachydactyly, facial features, pseudomuscular hypertrophy, joint limitation and hearing loss. We identified SMAD4 mutations as the cause of Myhre syndrome. SMAD4 mutations have also been identified in laryngotracheal stenosis, arthropathy, prognathism and short stature syndrome (LAPS). This study aimed to review the features of Myhre and LAPS patients to define the clinical spectrum of SMAD4 mutations. We included 17 females and 15 males ranging in age from 8 to 48 years. Thirty were diagnosed with Myhre syndrome and two with LAPS. SMAD4 coding sequence was analyzed by Sanger sequencing. Clinical and radiological features were collected from a questionnaire completed by the referring physicians. All patients displayed a typical facial gestalt, thickened skin, joint limitation and muscular pseudohypertrophy. Growth retardation was common (68.7%) and was variable in severity (from -5.5 to -2 SD), as was mild-to-moderate intellectual deficiency (87.5%) with additional behavioral problems in 56.2% of the patients. Significant health concerns like obesity, arterial hypertension, bronchopulmonary insufficiency, laryngotracheal stenosis, pericarditis and early death occurred in four. Twenty-nine patients had a de novo heterozygous SMAD4 mutation, including both patients with LAPS. In 27 cases mutation affected Ile500 and in two cases Arg496. The three patients without SMAD4 mutations had typical findings of Myhre syndrome. Myhre-LAPS syndrome is a clinically homogenous condition with life threatening complications in the course of the disease. Our identification of SMAD4 mutations in 29/32 cases confirms that SMAD4 is the major gene responsible for Myhre syndrome.
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http://dx.doi.org/10.1038/ejhg.2013.288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200423PMC
November 2014