Publications by authors named "Jamal Ghoumid"

39 Publications

Novel missense mutations in PTCHD1 alter its plasma membrane subcellular localization and cause intellectual disability and autism spectrum disorder.

Hum Mutat 2021 Apr 15. Epub 2021 Apr 15.

UMR1253, iBrain, INSERM, University of Tours, Tours, France.

The X-linked PTCHD1 gene, encoding a synaptic membrane protein, has been involved in neurodevelopmental disorders with the description of deleterious genomic microdeletions or truncating coding mutations. Missense variants were also identified, however, without any functional evidence supporting their pathogenicity level. We investigated 13 missense variants of PTCHD1, including eight previously described (c.152G>A,p.(Ser51Asn); c.217C>T,p.(Leu73Phe); c.517A>G,p.(Ile173Val); c.542A>C,p.(Lys181Thr); c.583G>A,p.(Val195Ile); c.1076A>G,p.(His359Arg); c.1409C>A,p.(Ala470Asp); c.1436A>G,p.(Glu479Gly)), and five novel ones (c.95C>T,p.(Pro32Leu); c.95C>G,p.(Pro32Arg); c.638A>G,p.(Tyr213Cys); c.898G>C,p.(Gly300Arg); c.928G>C,p.(Ala310Pro)) identified in male patients with intellectual disability (ID) and/or autism spectrum disorder (ASD). Interestingly, several of these variants involve amino acids localized in structural domains such as transmembrane segments. To evaluate their potentially deleterious impact on PTCHD1 protein function, we performed in vitro overexpression experiments of the wild-type and mutated forms of PTCHD1-GFP in HEK 293T and in Neuro-2a cell lines as well as in mouse hippocampal primary neuronal cultures. We found that six variants impaired the expression level of the PTCHD1 protein, and were retained in the endoplasmic reticulum suggesting abnormal protein folding. Our functional analyses thus provided evidence of the pathogenic impact of missense variants in PTCHD1, which reinforces the involvement of the PTCHD1 gene in ID and in ASD.
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http://dx.doi.org/10.1002/humu.24208DOI Listing
April 2021

Smith-Magenis syndrome: Clinical and behavioral characteristics in a large retrospective cohort.

Clin Genet 2021 Apr 5;99(4):519-528. Epub 2021 Jan 5.

Department of Genetics, APHP Nord-Université de Paris Robert Debré University Hospital and INSERM U1141 NeuroDiderot, Paris, France.

Smith-Magenis syndrome (SMS), characterized by dysmorphic features, neurodevelopmental disorder, and sleep disturbance, is due to an interstitial deletion of chromosome 17p11.2 (90%) or to point mutations in the RAI1 gene. In this retrospective cohort, we studied the clinical, cognitive, and behavioral profile of 47 European patients with SMS caused by a 17p11.2 deletion. We update the clinical and neurobehavioral profile of SMS. Intrauterine growth was normal in most patients. Prenatal anomalies were reported in 15%. 60% of our patients older than 10 years were overweight. Prevalence of heart defects (6.5% tetralogy of Fallot, 6.5% pulmonary stenosis), ophthalmological problems (89%), scoliosis (43%), or deafness (32%) were consistent with previous reports. Epilepsy was uncommon (2%). We identified a high prevalence of obstipation (45%). All patients had learning difficulties and developmental delay, but ID range was wide and 10% of patients had IQ in the normal range. Behavioral problems included temper tantrums and other difficult behaviors (84%) and night-time awakenings (86%). Optimal care of SMS children is multidisciplinary and requires important parental involvement. In our series, half of patients were able to follow adapted schooling, but 70% of parents had to adapt their working time, illustrating the medical, social, educative, and familial impact of having a child with SMS.
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http://dx.doi.org/10.1111/cge.13906DOI Listing
April 2021

De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy.

Genet Med 2021 Apr 10;23(4):653-660. Epub 2020 Dec 10.

Institute of Child Health, University Collge London, London, UK.

Purpose: This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals.

Methods: Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed.

Results: The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex.

Conclusion: We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed "SNAREopathies."
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http://dx.doi.org/10.1038/s41436-020-01020-wDOI Listing
April 2021

Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum.

Am J Med Genet A 2021 01 7;185(1):15-25. Epub 2020 Oct 7.

Department of Paediatric Neurology, University Hospital of Wales, Cardiff, UK.

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.
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http://dx.doi.org/10.1002/ajmg.a.61907DOI Listing
January 2021

Associations between cognitive performance and the rehabilitation, medical care and social support provided to French children with Prader-Willi syndrome.

Eur J Med Genet 2020 Dec 28;63(12):104064. Epub 2020 Sep 28.

Clinical Investigation Centre, INSERM 1432 - Clinical Epidemiology, Faculty of Medicine, Dijon University Hospital, France.

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with a characteristic behavioural phenotype. A multidisciplinary approach to care is required to prevent multiple medical complications in individuals affected by PWS. The aim of this study was to describe the rehabilitation, medical care, educational and social support provided to school-aged French PWS patients with varying neuropsychological profiles. Data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Nineteen PWS subjects with a mean age of 9.2 years were included. The mean full-scale intellectual quotient (IQ) was 58 (Wechsler scale). There were frequent dissociations between verbal and performance IQ that were not associated with a specific profile. We also observed lower autonomy and communication scores (5.3 years and 5.9 years equivalent, respectively, Vineland scale), the absence of hyperactivity (Conners scale), and the presence of behavioural abnormalities (CBCL scale). Multidisciplinary medical supervision was generally coordinated by the paediatric endocrinologist and did not always include follow-up with all of the recommended specialists, in particular with a paediatric psychiatrist. Analysis of multidisciplinary rehabilitation conducted in public and private-sector establishment revealed failings in psychological support, occupational therapy and dietary follow-up. Regarding education, most children younger than 10 years were in normal schools, while older individuals were often cared for in medico-social institutions. In conclusion, children and adolescents with PWS generally received appropriate care. Though there have been considerable improvements in the management of children with PWS, reference centres should continue reinforcing the coordination of multidisciplinary supervision.
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http://dx.doi.org/10.1016/j.ejmg.2020.104064DOI Listing
December 2020

Phenotypic spectrum of SHANK2-related neurodevelopmental disorder.

Eur J Med Genet 2020 Dec 25;63(12):104072. Epub 2020 Sep 25.

CHU Lille, Clinique de Génétique, Guy Fontaine, F-59000, Lille, France. Electronic address:

SHANK2 code a scaffolding protein located at the postsynaptic membrane of glutamatergic neurons. To date, only nine patients were reported with a SHANK2-variation or microdeletion. Molecular anomalies were identified through screening of large cohorts of patients, but only poor patient clinical descriptions were available. However, this information is crucial for patient care. Here, we describe two additional unrelated patients carrying a SHANK2 de novo variant, improving the delineation of the condition. Phenotypic analysis of these 11 patients identified as major features of the condition: mild to moderate intellectual disability, speech delay, poor language skills, and autism spectrum disorders.
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http://dx.doi.org/10.1016/j.ejmg.2020.104072DOI Listing
December 2020

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.

Brain 2020 10;143(10):2929-2944

Division of Neurology, Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, USA.

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.
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http://dx.doi.org/10.1093/brain/awz307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780481PMC
October 2020

Biallelic variants in GLE1 with survival beyond neonatal period.

Clin Genet 2020 12 20;98(6):622-625. Epub 2020 Sep 20.

Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.

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http://dx.doi.org/10.1111/cge.13841DOI Listing
December 2020

Confirmation of risk of cancer in blepharocheilodontic syndrome.

Genet Med 2020 10 2;22(10):1727-1728. Epub 2020 Jun 2.

Université de Lille, EA7364 RADEME, Lille, France.

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http://dx.doi.org/10.1038/s41436-020-0849-7DOI Listing
October 2020

Further delineation of the female phenotype with KDM5C disease causing variants: 19 new individuals and review of the literature.

Clin Genet 2020 07 29;98(1):43-55. Epub 2020 May 29.

INSERM UMR1231, Equipe Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.

X-linked intellectual disability (XLID) is a genetically heterogeneous condition involving more than 100 genes. To date, 35 pathogenic variants have been reported in the lysine specific demethylase 5C (KDM5C) gene. KDM5C variants are one of the major causes of moderate to severe XLID. Affected males present with short stature, distinctive facial features, behavioral disorders, epilepsy, and spasticity. For most of these variants, related female carriers have been reported, but phenotypic descriptions were poor. Here, we present clinical and molecular features of 19 females carrying 10 novel heterozygous variants affecting KDM5C function, including five probands with de novo variants. Four heterozygous females were asymptomatic. All affected individuals presented with learning disabilities or ID (mostly moderate), and four also had a language impairment mainly affecting expression. Behavioral disturbances were frequent, and endocrine disorders were more frequent in females. In conclusion, our findings provide evidence of the role of KDM5C in ID in females highlighting the increasing implication of XLID genes in females, even in sporadic affected individuals. Disease expression of XLID in females should be taken into consideration for genetic counseling.
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http://dx.doi.org/10.1111/cge.13755DOI Listing
July 2020

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

Hum Mutat 2020 07 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

Neurodevelopmental phenotype associated with CHD8-SUPT16H duplication.

Neurogenetics 2020 01 10;21(1):67-72. Epub 2019 Dec 10.

Institut de Génétique Médicale, CHU Lille, F-59000, Lille, France.

Microdeletions encompassing 14q11.2 locus, involving SUPT16H and CHD8, were shown to cause developmental delay, intellectual disability, autism spectrum disorders and macrocephaly. Variations leading to CHD8 haploinsufficiency or loss of function were also shown to lead to a similar phenotype. Recently, a 14q11.2 microduplication syndrome, encompassing CHD8 and SUPT16H, has been described, highlighting the importance of a tight control of at least CHD8 gene-dosage for a normal development. There have been only a few reports of 14q11.2 microduplications. Patients showed variable neurodevelopmental issues of variable severity. Breakpoints of the microduplications were non-recurrent, making interpretation of the CNV and determination of their clinical relevance difficult. Here, we report on two patients with 14q11.2 microduplication encompassing CHD8 and SUPT16H, one of whom had normal intelligence. Review of previous reports describing patients with comparable microduplications allowed for a more precise delineation of the condition and widening of the phenotypic spectrum.
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http://dx.doi.org/10.1007/s10048-019-00599-wDOI Listing
January 2020

Mayer-Rokitansky-Künster-Hauser syndrome due to 2q12.1q14.1 deletion: PAX8 the causing gene?

Eur J Med Genet 2020 Apr 12;63(4):103812. Epub 2019 Nov 12.

CHU Lille, Institut de Génétique Médicale, F-59000, Lille, France; CHU Lille, Clinique de Génétique - Guy Fontaine, F-59000, Lille, France. Electronic address:

Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) is a rare malformative disorder, characterized by congenital aplasia of the uterus and the upper two thirds of the vagina (MIM #277000). For a majority of patients, the disorder remained without identified genetic cause. However, four recurrent microdeletions, i.e. 1q21.1-16p11.2-17q12 and 22q11.21, as well as variants in genes contained in these loci, have been identified in a small number of cases. We describe an additional patient with 2q12.1q14.1 microdeletion, showing MRKH and congenital hypothyroidism due to thyroid gland hypoplasia. The patient received a dual diagnosis with microdeletion of SHOX locus in addition to the 2q12.1q14.1 microdeletion. Literature review and database analysis has enabled us to identify 5 OMIM morbid genes: CKAP2L, IL1B, IL1RN, IL36RN and PAX8. Among these, PAX8 (Paired Box Gene 8), a transcriptional factor part of the paired-box family, plays a key role in the development of the thyroid gland, kidneys and Müllerian derivatives. We discuss here the role of PAX8 and speculate on the possible involvement of PAX8 in MRKH. In this study, we report a second case of 2q12.1q14.1 microdeletion, involving PAX8 as a gene associated with Müllerian agenesis in a MRKH I and hypothyroidism. Further studies will confirm the direct participation of PAX8 in gene target sequencing in a population of MRKH with hypothyroidism.
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http://dx.doi.org/10.1016/j.ejmg.2019.103812DOI Listing
April 2020

Phenotypic and genetic spectrum of alveolar capillary dysplasia: a retrospective cohort study.

Arch Dis Child Fetal Neonatal Ed 2020 Jul 22;105(4):387-392. Epub 2019 Oct 22.

Clinical Genetics, CHU Nancy, Nancy, France.

Objective: Alveolar capillary dysplasia (ACD) is one of the causes of pulmonary hypertension. Its diagnosis is histological but new pathogenetic data have emerged. The aim of this study was to describe a French cohort of patients with ACD to improve the comprehension and the diagnosis of this pathology which is probably underdiagnosed.

Methods: A retrospective observational study was conducted in French hospitals. Patients born between 2005 and 2017, whose biological samples were sent to the French genetic reference centres, were included. Clinical, histological and genetic data were retrospectively collected.

Results: We presented a series of 21 patients. The mean of postmenstrual age at birth was 37.6 weeks. The first symptoms appeared on the median of 2.5 hours. Pulmonary hypertension was diagnosed in 20 patients out of 21. Two cases had prolonged survival (3.3 and 14 months). Histological analysis was done on lung tissue from autopsy (57.1% of cases) or from percutaneous biopsy (28.6%). was found abnormal in 15 patients (71.4%): 8 deletions and 7 point mutations. Two deletions were found by chromosomal microarray.

Conclusion: This study is one of the largest clinically described series in literature. It seems crucial to integrate genetics early into diagnostic support. We propose a diagnostic algorithm for helping medical teams to improve diagnosis of this pathology.
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http://dx.doi.org/10.1136/archdischild-2019-317121DOI Listing
July 2020

Multiplex targeted high-throughput sequencing in a series of 352 patients with congenital limb malformations.

Hum Mutat 2020 01 23;41(1):222-239. Epub 2019 Sep 23.

Service de Biochimie et Biologie Moléculaire, CHU Lille, Lille, France.

Congenital limb malformations (CLM) comprise many conditions affecting limbs and more than 150 associated genes have been reported. Due to this large heterogeneity, a high proportion of patients remains without a molecular diagnosis. In the last two decades, advances in high throughput sequencing have allowed new methodological strategies in clinical practice. Herein, we report the screening of 52 genes/regulatory sequences by multiplex high-throughput targeted sequencing, in a series of 352 patients affected with various CLM, over a 3-year period of time. Patients underwent a clinical triage by expert geneticists in CLM. A definitive diagnosis was achieved in 35.2% of patients, the yield varying considerably, depending on the phenotype. We identified 112 single nucleotide variants and 26 copy-number variations, of which 52 are novel pathogenic or likely pathogenic variants. In 6% of patients, variants of uncertain significance have been found in good candidate genes. We showed that multiplex targeted high-throughput sequencing works as an efficient and cost-effective tool in clinical practice for molecular diagnosis of congenital limb malformations. Careful clinical evaluation of patients may maximize the yield of CLM panel testing.
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http://dx.doi.org/10.1002/humu.23912DOI Listing
January 2020

The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis.

Genet Med 2020 02 7;22(2):389-397. Epub 2019 Aug 7.

Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Purpose: Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function.

Methods: We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains.

Results: The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains.

Conclusion: The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.
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http://dx.doi.org/10.1038/s41436-019-0612-0DOI Listing
February 2020

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

Difficulties adapting to Nail-Patella syndrome: A qualitative study of patients' perspectives.

J Genet Couns 2019 10 16;28(5):1011-1020. Epub 2019 Jul 16.

Center of Clinical Psychology, Psychopathology and Psychosomatic Research, Free University of Brussels, Brussels, Belgium.

Nail-Patella syndrome (NPS) is a genetic disorder generating physical malformations and, in approximately one in three cases, ocular and renal damage. The present research aimed to deeply understand patients' subjective experience with NPS, particularly the aspects of the syndrome that affect patients' adaptation and to propose interventions that can improve genetic and psychological counseling and help patients cope with their condition. Semi-structured interviews of nine people diagnosed with NPS were analyzed using interpretative phenomenological analysis. Results highlighted attempts to look like a person without disabilities by hiding malformations and not telling the truth about symptoms' genetic origin because of patients' poor self-esteem, negative self-cognition, and social isolation experienced from childhood to adulthood. Difficulties of adaptation to physical limits and pain were also identified. The majority of participants who were not diagnosed at birth tended to consider physical symptoms as "birth malformations" without imagining other potential implications until receiving a diagnosis. Despite the diagnosis, the majority continued to minimize the potential complications by considering NPS as a "physical difference" and not adhering to medical surveillance.
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http://dx.doi.org/10.1002/jgc4.1153DOI Listing
October 2019

Serpin B1 defect and increased apoptosis of neutrophils in Cohen syndrome neutropenia.

J Mol Med (Berl) 2019 05 7;97(5):633-645. Epub 2019 Mar 7.

Inserm UMR1170, Gustave Roussy Cancer Center, F-94800, Villejuif, France.

Cohen syndrome (CS) is a rare genetic disorder due to mutations in VPS13B gene. Among various clinical and biological features, CS patients suffer from inconsistent neutropenia, which is associated with recurrent but minor infections. We demonstrate here that this neutropenia results from an exaggerate rate of neutrophil apoptosis. Besides this increased cell death, which occurs in the absence of any endoplasmic reticulum stress or defect in neutrophil elastase (ELANE) expression or localization, all neutrophil functions appeared to be normal. We showed a disorganization of the Golgi apparatus in CS neutrophils precursors, that correlates with an altered glycosylation of ICAM-1 in these cells, as evidenced by a migration shift of the protein. Furthermore, a striking decrease in the expression of SERPINB1 gene, which encodes a critical component of neutrophil survival, was detected in CS neutrophils. These abnormalities may account for the excessive apoptosis of neutrophils leading to neutropenia in CS. KEY MESSAGES: Cohen syndrome patients' neutrophils display normal morphology and functions. Cohen syndrome patients' neutrophils have an increased rate of spontaneous apoptosis compared to healthy donors' neutrophils. No ER stress or defective ELA2 expression or glycosylation was observed in Cohen syndrome patients' neutrophils. SerpinB1 expression is significantly decreased in Cohen syndrome neutrophils as well as in VPS13B-deficient cells.
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http://dx.doi.org/10.1007/s00109-019-01754-4DOI Listing
May 2019

Identification and Characterization of Known Biallelic Mutations in the () Gene in a Novel Family With Bardet-Biedl Syndrome.

Front Genet 2019 30;10:21. Epub 2019 Jan 30.

Laboratoire de Génétique Médicale, Institut de Génétique Médicale d'Alsace, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France.

Bardet-Biedl syndrome (BBS; MIM 209900) is a rare ciliopathy characterized by retinitis pigmentosa, postaxial polydactyly, obesity, hypogonadism, cognitive impairment and kidney dysfunction. Mutations in 22 BBS genes have been identified to cause the disease. We report a family with typical BBS features (retinitis pigmentosa, postaxial polydactyly, obesity, cognitive impairment, and atrioventricular septal defect) mutated in . IFT27 is part of the Intraflagellar transport (IFT), a bidirectional mechanism allowing the protein motility within the cilia. Using whole exome sequencing, two compound heterozygous mutations were found in the proband (NM_006860.4:c.[104A > G];[349+1G > T], p.[Tyr35Cys];[?]) consistent with the expected autosomal recessive inheritance mode. These two mutations have already been reported but independently in other families and lacking either familial segregation or functional validation. This is the third report of mutations in BBS patients confirming as a BBS gene (). Mutations in IFT genes ( and ) confirm the IFT-pathway as a pathomechanism for BBS.
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http://dx.doi.org/10.3389/fgene.2019.00021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363664PMC
January 2019

Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants.

Eur J Hum Genet 2019 03 14;27(3):360-368. Epub 2018 Dec 14.

CHU Lille, Clinique de Génétique, 59000, Lille, France.

Holt-Oram syndrome (HOS) is an autosomal dominant condition characterised by the association of congenital heart defect (CHD), with or without rhythm disturbances and radial defects, due to TBX5 variants. The diagnosis is challenged by the variability of expression and the large phenotypic overlap with other conditions, like Okihiro syndrome, TAR syndrome or Fanconi disease. We retrospectively reviewed 212 patients referred for suspicion of HOS between 2002 and 2014, who underwent TBX5 screening. A TBX5 variant has been identified in 78 patients, representing the largest molecular series ever described. In the cohort, 61 met the previously described diagnostic criteria and 17 have been considered with an uncertain HOS diagnosis. A CHD was present in 91% of the patients with a TBX5 variant, atrial septal defects being the most common (61.5%). The genotype-phenotype study highlights the importance of some critical features in HOS: the septal characteristic of the CHD, the bilateral and asymmetric characteristics of the radial defect and the presence of shoulder or elbow mobility defect. Besides, 21 patients presented with an overlapping condition. Among them, 13 had a typical HOS presentation. We discuss the strategies that could be adopted to improve the molecular delineation of the remaining typical patients.
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http://dx.doi.org/10.1038/s41431-018-0303-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460573PMC
March 2019

Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability.

Eur J Hum Genet 2019 02 5;27(2):278-290. Epub 2018 Oct 5.

Department of Otorhinolaryngology-Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium.

Deletions on chromosome 15q14 are a known chromosomal cause of cleft palate, typically co-occurring with intellectual disability, facial dysmorphism, and congenital heart defects. The identification of patients with loss-of-function variants in MEIS2, a gene within this deletion, suggests that these features are attributed to haploinsufficiency of MEIS2. To further delineate the phenotypic spectrum of the MEIS2-related syndrome, we collected 23 previously unreported patients with either a de novo sequence variant in MEIS2 (9 patients), or a 15q14 microdeletion affecting MEIS2 (14 patients). All but one de novo MEIS2 variant were identified by whole-exome sequencing. One variant was found by targeted sequencing of MEIS2 in a girl with a clinical suspicion of this syndrome. In addition to the triad of palatal defects, heart defects, and developmental delay, heterozygous loss of MEIS2 results in recurrent facial features, including thin and arched eyebrows, short alae nasi, and thin vermillion. Genotype-phenotype comparison between patients with 15q14 deletions and patients with sequence variants or intragenic deletions within MEIS2, showed a higher prevalence of moderate-to-severe intellectual disability in the former group, advocating for an independent locus for psychomotor development neighboring MEIS2.
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http://dx.doi.org/10.1038/s41431-018-0281-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336847PMC
February 2019

Novel mutations in the ciliopathy-associated gene CPLANE1 (C5orf42) cause OFD syndrome type VI rather than Joubert syndrome.

Eur J Med Genet 2018 Oct 30;61(10):585-595. Epub 2018 Mar 30.

Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran.

Mutations in CPLANE1 (previously known as C5orf42) cause Oral-Facial-Digital Syndrome type VI (OFD6) as well as milder Joubert syndrome (JS) phenotypes. Seven new cases from five unrelated families diagnosed with pure OFD6 were systematically examined. Based on the clinical manifestations of these patients and those described in the literature, we revised the diagnostic features of OFD6 and include the seven most common characteristics: 1) molar tooth sign, 2) tongue hamartoma and/or lobulated tongue, 3) additional frenula, 4) mesoaxial polydactyly of hands, 5) preaxial polydactyly of feet, 6) syndactyly and/or bifid toe, and 7) hypothalamic hamartoma. By whole or targeted exome sequencing, we identified seven novel germline recessive mutations in CPLANE1, including missense, nonsense, frameshift and canonical splice site variants, all causing OFD6 in these patients. Since CPLANE1 is also mutated in JS patients, we examined whether a genotype-phenotype correlation could be established. We gathered and compared 46 biallelic CPLANE1 mutations reported in 32 JS and 26 OFD6 patients. Since no clear correlation between paired genotypes and clinical outcomes could be determined, we concluded that patient's genetic background and gene modifiers may modify the penetrance and expressivity of CPLANE1 causal alleles. To conclude, our study provides a comprehensive view of the phenotypic range, the genetic basis and genotype-phenotype association in OFD6 and JS. The updated phenotype scoring system together with the identification of new CPLANE1 mutations will help clinicians and geneticists reach a more accurate diagnosis for JS-related disorders.
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http://dx.doi.org/10.1016/j.ejmg.2018.03.012DOI Listing
October 2018

MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype.

Neurogenetics 2018 05 6;19(2):93-103. Epub 2018 Mar 6.

Service de Génétique et Inserm U1079, Centre Normand de Génomique Médicale et Médecine Personnalisée, CHU de Rouen, Inserm et Université de Rouen, Rouen, France.

Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.
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http://dx.doi.org/10.1007/s10048-018-0541-0DOI Listing
May 2018

Arterial tortuosity syndrome: 40 new families and literature review.

Genet Med 2018 10 11;20(10):1236-1245. Epub 2018 Jan 11.

Pediatrics Department, Kuwait University, Kuwait City, Kuwait.

Purpose: We delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10.

Methods: We retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-β signaling with immunohistochemistry for pSMAD2 and CTGF.

Results: Stenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-β signaling.

Conclusion: Our findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities.
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http://dx.doi.org/10.1038/gim.2017.253DOI Listing
October 2018

Molecular and cellular issues of KMT2A variants involved in Wiedemann-Steiner syndrome.

Eur J Hum Genet 2018 01 4;26(1):107-116. Epub 2017 Dec 4.

Inserm, Institut Cochin, U1016, Paris, France.

Variants in KMT2A, encoding the histone methyltransferase KMT2A, are a growing cause of intellectual disability (ID). Up to now, the majority of KMT2A variants are non-sense and frameshift variants causing a typical form of Wiedemann-Steiner syndrome. We studied KMT2A gene in a cohort of 200 patients with unexplained syndromic and non-syndromic ID and identified four novel variants, one splice and three missense variants, possibly deleterious. We used primary cells from the patients and molecular approaches to determine the deleterious effects of those variants on KMT2A expression and function. For the putative splice variant c.11322-1G>A, we showed that it led to only one nucleotide deletion and loss of the C-terminal part of the protein. For two studied KMT2A missense variants, c.3460C>T (p.(Arg1154Trp)) and c.8558T>G (p.(Met2853Arg)), located at the cysteine-rich CXXC domain and the transactivation domain of the protein, respectively, we found altered KMT2A target genes expression in patient's fibroblasts compared to controls. Furthermore, we found a disturbed subcellular distribution of KMT2A for the c.3460C>T mutant. Taken together, our results demonstrated the deleterious impact of the splice variant and of the missense variants located at two different functional domains and suggested reduction of KMT2A function as the disease-causing mechanism.
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http://dx.doi.org/10.1038/s41431-017-0033-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839021PMC
January 2018

Cerebellar hypoplasia with endosteal sclerosis is a POLR3-related disorder.

Eur J Hum Genet 2017 08 7;25(8):1011-1014. Epub 2017 Jun 7.

Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHU Lille, Lille, France.

CHES (cerebellar hypoplasia with endosteal sclerosis) syndrome (OMIM#213002) associates hypomyelination, cerebellar atrophy, hypogonadism and hypodontia. So far, only five patients have been described. The condition is of neonatal onset. Patients have severe psychomotor delay and moderate to severe intellectual disability. Inheritance is assumed to be autosomal recessive due to recurrence in sibs, consanguinity of parents and absence of vertical transmission. CHES syndrome is reminiscent of 4H-leukodystrophy, a recessive-inherited affection due to variations in genes encoding subunits of the RNA polymerase III (POLR3A-POLR3B-POLR1C). POLR3B variants have been identified in one CHES patient. Here we report on a novel CHES patient, carrying compound heterozygous variations in POLR3B. This report confirms affiliation of CHES to POLR3-related disorders and suggests that CHES syndrome represents a severe form of 4H-leukodystrophy.
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http://dx.doi.org/10.1038/ejhg.2017.73DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567146PMC
August 2017