A tale of two anomalies. A paternal duplication and a maternal deletion of 15q13
BULK, Saskia ; Decortis, Thierry ; et al
Poster (2015, March 06)Detailed reference viewed: 12 (1 ULg)
Congenital gigantism in a girl with anterior pituitary hyperplasia : a new genes for a new disease
; Daly, Adrian ; et al
in Abstract book - 43ème Congrès Annuel de la Société Belge de Pédiatrie (2015, March)Detailed reference viewed: 18 (0 ULg)
X-Linked acro-gigantism (X-LAG) syndrome : a new form of infant-onset pituitary gigantism
; ; Rostomyan, Liliya et al
in Abstract book - 14th International Pituitary Congress (2015, March)Detailed reference viewed: 17 (0 ULg)
Disease characteristics of patients with X-linked acrogigantism (X-LAG) syndrome
Daly, Adrian ; ; et al
in Abstract book - ENDO 2015 (2015, March)Detailed reference viewed: 25 (6 ULg)
X-Linked acro-gigantism (X-LAG) due to microduplications of chromosome Xq26 : A new disorder and implications for acromegaly
; ; et al
in Abstract book - ENDO 2015 (2015, March)Detailed reference viewed: 15 (2 ULg)
X-linked acrogigantism (X-LAG) syndrome : Clinical Profile and Therapeutic responses
Beckers, Albert ; ; et al
in Endocrine-Related Cancer (2015), 22Detailed reference viewed: 8 (3 ULg)
Mutation of the iron-sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy.
DEBRAY, François-Guillaume ; ; et al
in Journal of inherited metabolic disease (2015)
Leukodystrophies are a heterogeneous group of severe genetic neurodegenerative disorders. A multiple mitochondrial dysfunctions syndrome was found in an infant presenting with a progressive ... [more ▼]
Leukodystrophies are a heterogeneous group of severe genetic neurodegenerative disorders. A multiple mitochondrial dysfunctions syndrome was found in an infant presenting with a progressive leukoencephalopathy. Homozygosity mapping, whole exome sequencing, and functional studies were used to define the underlying molecular defect. Respiratory chain studies in skeletal muscle isolated from the proband revealed a combined deficiency of complexes I and II. In addition, western blotting indicated lack of protein lipoylation. The combination of these findings was suggestive for a defect in the iron-sulfur (Fe/S) protein assembly pathway. SNP array identified loss of heterozygosity in large chromosomal regions, covering the NFU1 and BOLA3, and the IBA57 and ABCB10 candidate genes, in 2p15-p11.2 and 1q31.1-q42.13, respectively. A homozygous c.436C > T (p.Arg146Trp) variant was detected in IBA57 using whole exome sequencing. Complementation studies in a HeLa cell line depleted for IBA57 showed that the mutant protein with the semi-conservative amino acid exchange was unable to restore the biochemical phenotype indicating a loss-of-function mutation of IBA57. In conclusion, defects in the Fe/S protein assembly gene IBA57 can cause autosomal recessive neurodegeneration associated with progressive leukodystrophy and fatal outcome at young age. In the affected patient, the biochemical phenotype was characterized by a defect in the respiratory chain complexes I and II and a decrease in mitochondrial protein lipoylation, both resulting from impaired assembly of Fe/S clusters. [less ▲]Detailed reference viewed: 7 (4 ULg)
Diagnostic pitfall in antenatal manifestations of CPT II deficiency.
BOEMER, François ; DEBERG, Michelle ; SCHOOS, Roland et al
in Clinical genetics (2015)
Carnitine palmitoyltransferase II (CPT2) deficiency is a rare inborn error of mitochondrial fatty acid metabolism associated with various phenotypes. Whereas most patients present with postnatal signs of ... [more ▼]
Carnitine palmitoyltransferase II (CPT2) deficiency is a rare inborn error of mitochondrial fatty acid metabolism associated with various phenotypes. Whereas most patients present with postnatal signs of energetic failure affecting muscle and liver, a small subset of patients presents antenatal malformations including brain dysgenesis and neuronal migration defects. Here, we report recurrence of severe cerebral dysgenesis with Dandy-Walker malformation in three successive pregnancies and review previously reported antenatal cases. Interestingly, we also report that acylcarnitines profile, tested retrospectively on the amniotic fluid of last pregnancy, was not sensitive enough to allow reliable prenatal diagnosis of CPT2 deficiency. Finally, because fetuses affected by severe cerebral malformations are frequently aborted, CPT2 deficiency may be underestimated and fatty acid oxidation disorders should be considered when faced with a fetus with Dandy-Walker anomaly or another brain dysgenesis. [less ▲]Detailed reference viewed: 16 (5 ULg)
Evaluation of the distal 22q11 deletion syndrome. A highly variable phenotype
BULK, Saskia ; PIERQUIN, Geneviève ; GAILLEZ, Stephanie et al
Poster (2014, February 07)Detailed reference viewed: 23 (6 ULg)
Haematological and molecular responses in refractory anaemia with ring sideroblasts and thrombocytosis treated with lenalidomide
CAERS, Jo ; HAFRAOUI, Kaoutar ; KEUTGENS, Aurore et al
in European Journal of Haematology (2014), 92(2), 179-180Detailed reference viewed: 71 (31 ULg)
Implementation of genomic arrays in prenatal diagnosis: the Belgian approach to meet the challenges.
; ; et al
in European journal of medical genetics (2014), 57(4), 151-6
After their successful introduction in postnatal testing, genome-wide arrays are now rapidly replacing conventional karyotyping in prenatal diagnostics. While previous studies have demonstrated the ... [more ▼]
After their successful introduction in postnatal testing, genome-wide arrays are now rapidly replacing conventional karyotyping in prenatal diagnostics. While previous studies have demonstrated the advantages of this method, we are confronted with difficulties regarding the technology and the ethical dilemmas inherent to genomic arrays. These include indication for testing, array design, interpretation of variants and how to deal with variants of unknown significance and incidental findings. The experiences with these issues reported in the literature are most often from single centres. Here, we report on a national consensus approach how microarray is implemented in all genetic centres in Belgium. These recommendations are subjected to constant re-evaluation based on our growing experience and can serve as a useful tool for those involved in prenatal diagnosis. [less ▲]Detailed reference viewed: 30 (6 ULg)
Array-CGH analysis in Rwandan patients presenting development delay/intellectual disability with multiple congenital anomalies.
; CABERG, Jean-Hubert ; et al
in BMC medical genetics (2014), 15(1), 79
BACKGROUND: Array-CGH is considered as the first-tier investigation used to identify copy number variations. Right now, there is no available data about the genetic etiology of patients with development ... [more ▼]
BACKGROUND: Array-CGH is considered as the first-tier investigation used to identify copy number variations. Right now, there is no available data about the genetic etiology of patients with development delay/intellectual disability and congenital malformation in East Africa. METHODS: Array comparative genomic hybridization was performed in 50 Rwandan patients with development delay/intellectual disability and multiple congenital abnormalities, using the Agilent's 180 K microarray platform. RESULTS: Fourteen patients (28%) had a global development delay whereas 36 (72%) patients presented intellectual disability. All patients presented multiple congenital abnormalities. Clinically significant copy number variations were found in 13 patients (26%). Size of CNVs ranged from 0,9 Mb to 34 Mb. Six patients had CNVs associated with known syndromes, whereas 7 patients presented rare genomic imbalances. CONCLUSION: This study showed that CNVs are present in African population and show the importance to implement genetic testing in East-African countries. [less ▲]Detailed reference viewed: 18 (10 ULg)
Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation.
; Daly, Adrian ; et al
in The New England journal of medicine (2014)
Background Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. Methods We performed ... [more ▼]
Background Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. Methods We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly. Results We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients' pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells. Conclusions We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.). [less ▲]Detailed reference viewed: 45 (27 ULg)
Severe dystonia, cerebellar atrophy, and cardiomyopathy likely caused by a missense mutation in TOR1AIP1.
; ; et al
in Orphanet journal of rare diseases (2014), 9(1), 174
BackgroundDystonia, cerebellar atrophy, and cardiomyopathy constitute a rare association.MethodsWe used homozygosity mapping and whole exome sequencing to determine the mutation, western blot and ... [more ▼]
BackgroundDystonia, cerebellar atrophy, and cardiomyopathy constitute a rare association.MethodsWe used homozygosity mapping and whole exome sequencing to determine the mutation, western blot and immunolabelling on cultured fibroblasts to demonstrate the lower expression and the mislocalization of the protein.ResultsWe report on a boy born from consanguineous healthy parents, who presented at three years of age with rapidly progressing dystonia, progressive cerebellar atrophy, and dilated cardiomyopathy. We identified regions of homozygosity and performed whole exome sequencing that revealed a homozygous missense mutation in TOR1AIP1. The mutation, absent in controls, results in a change of a highly conserved glutamic acid to alanine. TOR1AIP1 encodes lamina-associated polypeptide 1 (LAP1), a transmembrane protein ubiquitously expressed in the inner nuclear membrane. LAP1 interacts with torsinA, the protein mutated in DYT1-dystonia. In vitro studies in fibroblasts of the patient revealed reduced expression of LAP1 and its mislocalization and aggregation in the endoplasmic reticulum as underlying pathogenic mechanisms.Conclusions and relevanceThe pathogenic role of TOR1AIP1 mutation is supported by a) the involvement of a highly conserved amino acid, b) the absence of the mutation in controls, c) the functional interaction of LAP1 with torsinA, and d) mislocalization of LAP1 in patient cells. Of note, cardiomyopathy has been reported in LAP1-null mice and in patients with the TOR1AIP1 nonsense mutation. Other cases will help delineate the clinical spectrum of LAP1-related mutations. [less ▲]Detailed reference viewed: 13 (2 ULg)
Femoral-facial syndrome: long term follow-up and associated array CGH abnormalities.
JACQUINET, Adeline ; VALDES SOCIN, Hernan Gonzalo ; LIBIOULLE, Cécile et al
Poster (2013, October 22)
The femoral-facial syndrome is usually sporadic and its aetiology remains unknown. Non-genetic factors as maternal diabetes mellitus have been associated. Reports of familial cases have otherwise ... [more ▼]
The femoral-facial syndrome is usually sporadic and its aetiology remains unknown. Non-genetic factors as maternal diabetes mellitus have been associated. Reports of familial cases have otherwise suggested autosomal dominant inheritance. We report the 20 years clinical follow-up of a girl with femoral-facial syndrome diagnosed at birth. Recently, array CGH investigation identified a 1400 kb duplication at 9q31.1, including the gene SMC2, and a 343 kb deletion at 12q24.33 including the genes CHFR, ZNF26, ZNF140, ZNF10 and ZNF268. Moreover, the patient presents a Mayer-Rokitansky-Kuster-Hauser syndrome diagnosed at puberty. Femoral-facial syndrome and Mullerian agenesis may reflect different defects in the primary axial mesodermal development, being the consequences of same environmental or/and genetic factors during blastogenesis. Among these genetic factors, we suggest the possible involvement of the two copy number variants reported here [less ▲]Detailed reference viewed: 70 (9 ULg)
Homozygosity mapping in clinical setting : a usefull method in workup of patients born to consanguineous parents presenting with an heterogeneous autosomal recessive disorder
SEGERS, Karin ; CABERG, Jean-Hubert ; JACQUINET, Adeline et al
Poster (2013, March 15)Detailed reference viewed: 16 (0 ULg)
Clinical, cytogenetic and molecular characterization of two cases of mosaic ring chromosome 13.
Uwineza, Annette ; PIERQUIN, Geneviève ; GAILLEZ, Stephanie et al
in Genetic counseling (Geneva, Switzerland) (2013), 24(2), 193-200
The occurrence of mosaic ring chromosome 13 is rare. The mechanism of ring chromosome formation is usually associated with loss of genetic material. We report 2 cases of mosaic ring chromosome 13 ... [more ▼]
The occurrence of mosaic ring chromosome 13 is rare. The mechanism of ring chromosome formation is usually associated with loss of genetic material. We report 2 cases of mosaic ring chromosome 13, resulting in deletion of 13qter. The first patient, a 15 year-old boy, presented a delayed psychomotor development, mental retardation, dysmorphic features and bleeding disorders associated with a de novo terminal 13q34 deletion. The second case was a foetus of 31 weeks with prenatal diagnosis of severe malformation such as holoprosencephaly, congenital cardiac defects, gastro-intestinal abnormalities with intrauterine growth retardation, the molecular analysis showed a de novo deletion encompassing the region 13q31.3-q34. [less ▲]Detailed reference viewed: 55 (9 ULg)
Genetic diagnosis of Duchenne and Becker muscular dystrophy using multiplex ligation-dependent probe amplification in Rwandan patients.
Uwineza, Annette ; ; et al
in Journal of tropical pediatrics (2013)
Duchenne and Becker muscular dystrophies are the most common clinical forms of muscular dystrophies. They are genetically X-linked diseases caused by a mutation in the dystrophin (DMD) gene. A genetic ... [more ▼]
Duchenne and Becker muscular dystrophies are the most common clinical forms of muscular dystrophies. They are genetically X-linked diseases caused by a mutation in the dystrophin (DMD) gene. A genetic diagnosis was carried out in six Rwandan patients presenting a phenotype of Duchenne and Becker muscular dystrophies and six asymptomatic female carrier relatives using multiplex ligation-dependent probe amplification (MLPA). Our results revealed deletion of the exons 48-51 in one patient, an inherited deletion of the exons 8-21 in two brothers and a de novo deletion of the exons 46-50 in the fourth patient. No copy number variation was found in two patients. Only one female carrier presented exon deletion in the DMD gene. This is the first cohort of genetic analysis in Rwandan patients affected by Duchenne and Becker muscular dystrophies. This report confirmed that MLPA assay can be easily implemented in low-income countries. [less ▲]Detailed reference viewed: 40 (18 ULg)