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1.
Neurogenetics ; 22(3): 207-213, 2021 07.
Article in English | MEDLINE | ID: mdl-33683518

ABSTRACT

A de novo 0.95 Mb 8p21.3 deletion had been identified in an individual with non-syndromic autism spectrum disorder (ASD) through high-resolution copy number variant analysis. Subsequent screening of in-house and publicly available databases resulted in the identification of six additional individuals with 8p21.3 deletions. Through case-based reasoning, we conclude that 8p21.3 deletions are rare causes of non-syndromic neurodevelopmental and neuropsychiatric disorders. Based on literature data, we highlight six genes within the region of minimal overlap as potential ASD genes or genes for neuropsychiatric disorders: DMTN, EGR3, FGF17, LGI3, PHYHIP, and PPP3CC.


Subject(s)
Autism Spectrum Disorder/genetics , DNA Copy Number Variations/genetics , Gene Deletion , Genetic Predisposition to Disease/genetics , Humans , Risk Factors
2.
Clin Dysmorphol ; 30(3): 121-124, 2021 Jul 01.
Article in English | MEDLINE | ID: mdl-33605605

ABSTRACT

Homozygous or compound heterozygous mutations in STRADA cause polyhydramnios, megalencephaly and symptomatic epilepsy syndrome (PMSE), with additional features of distinctive facial traits and severe developmental delay or intellectual disability. This syndrome was first defined in 16 Old Order Mennonite patients, carrying a homozygous STRADA deletion of exon 9-13. Five additional PMSE patients have been reported since, each of them with loss-of-function variants. We report a female patient with the typical clinical features of PMSE, homozygous for a novel STRADA missense mutation c.792T>A (p.Ser264Arg) in exon 10. This finding contributes to the further delineation of the phenotype of PMSE.


Subject(s)
Adaptor Proteins, Vesicular Transport/genetics , Adaptor Proteins, Vesicular Transport/metabolism , Epileptic Syndromes/genetics , Child , Developmental Disabilities/genetics , Epilepsy, Generalized/genetics , Female , Homozygote , Humans , Intellectual Disability/genetics , Megalencephaly/genetics , Mutation, Missense/genetics , Phenotype , Polyhydramnios/genetics , Pregnancy
3.
Eur J Med Genet ; 63(11): 104009, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32758660

ABSTRACT

Interstitial 19q13.11 deletions are associated with ectrodactyly, which has recently been linked to loss-of-function of the UBA2 gene. We report a boy with a de novo frameshift mutation in UBA2 (c.612delA (p.(Glu205Lysfs*63)), presenting with ectrodactyly of the feet associated with learning difficulties and minor physical anomalies. We review genotype-phenotype correlations in patients with chromosomal 19q13.11 microdeletions compared to those with intragenic UBA2 mutations.


Subject(s)
Abnormalities, Multiple/genetics , Chromosome Disorders/genetics , Limb Deformities, Congenital/genetics , Phenotype , Ubiquitin-Activating Enzymes/genetics , Abnormalities, Multiple/pathology , Child, Preschool , Chromosome Deletion , Chromosome Disorders/pathology , Frameshift Mutation , Genotype , Humans , Limb Deformities, Congenital/pathology , Male
4.
Article in English | MEDLINE | ID: mdl-28679690

ABSTRACT

Troyer syndrome (MIM#275900) is an autosomal recessive form of complicated hereditary spastic paraplegia. It is characterized by progressive lower extremity spasticity and weakness, dysarthria, distal amyotrophy, developmental delay, short stature, and subtle skeletal abnormalities. It is caused by deleterious mutations in the SPG20 gene, encoding spartin, on Chromosome 13q13. Until now, six unrelated families with a genetically confirmed diagnosis have been reported. Here we report the clinical findings in three brothers of a consanguineous Moroccan family, aged 24, 17, and 7 yr old, with spastic paraplegia, short stature, motor and cognitive delay, and severe intellectual disability. Targeted exon capture and sequencing showed a homozygous nonsense mutation in the SPG20 gene, c.1369C>T (p.Arg457*), in the three affected boys.


Subject(s)
Proteins/genetics , Spastic Paraplegia, Hereditary/genetics , Adolescent , Cell Cycle Proteins , Child , Codon, Nonsense/genetics , Exons , Female , Humans , Intellectual Disability/genetics , Male , Mutation , Pedigree , Proteins/metabolism , Siblings , Young Adult
5.
Eur J Med Genet ; 59(10): 499-501, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27633572

ABSTRACT

Smith-Magenis syndrome (SMS) is a contiguous-gene disorder most commonly caused by a deletion of chromosome 17p11.2. We report a 57 year-old man with SMS who presents bilateral renal tumors. This is most likely related to haploinsufficiency of FLCN gene, located in the deleted region, and a known tumor suppressor gene. Haploinsufficiency of FLCN causes Birt-Hogg-Dubé syndrome (BHDS), characterized by pulmonary cysts, renal and skin tumors. The present observation suggests that the follow-up of patients with SMS should also focus on possible manifestations of BHDS.


Subject(s)
Kidney Neoplasms/genetics , Proto-Oncogene Proteins/genetics , Skin Neoplasms/genetics , Smith-Magenis Syndrome/genetics , Tumor Suppressor Proteins/genetics , Birt-Hogg-Dube Syndrome/complications , Birt-Hogg-Dube Syndrome/genetics , Birt-Hogg-Dube Syndrome/pathology , Exons/genetics , Genetic Predisposition to Disease , Haploinsufficiency/genetics , Humans , Kidney/pathology , Kidney Neoplasms/complications , Kidney Neoplasms/pathology , Male , Middle Aged , Mutation , Sequence Deletion , Skin Neoplasms/complications , Skin Neoplasms/pathology , Smith-Magenis Syndrome/pathology
6.
Hum Mutat ; 37(8): 804-11, 2016 08.
Article in English | MEDLINE | ID: mdl-27159028

ABSTRACT

Intellectual disability (ID) is a heterogeneous disorder with an unknown molecular etiology in many cases. Previously, X-linked ID (XLID) studies focused on males because of the hemizygous state of their X chromosome. Carrier females are generally unaffected because of the presence of a second normal allele, or inactivation of the mutant X chromosome in most of their cells (skewing). However, in female ID patients, we hypothesized that the presence of skewing of X-inactivation would be an indicator for an X chromosomal ID cause. We analyzed the X-inactivation patterns of 288 females with ID, and found that 22 (7.6%) had extreme skewing (>90%), which is significantly higher than observed in the general population (3.6%; P = 0.029). Whole-exome sequencing of 19 females with extreme skewing revealed causal variants in six females in the XLID genes DDX3X, NHS, WDR45, MECP2, and SMC1A. Interestingly, variants in genes escaping X-inactivation presumably cause both XLID and skewing of X-inactivation in three of these patients. Moreover, variants likely accounting for skewing only were detected in MED12, HDAC8, and TAF9B. All tested candidate causative variants were de novo events. Hence, extreme skewing is a good indicator for the presence of X-linked variants in female patients.


Subject(s)
Genetic Variation , Intellectual Disability/genetics , Sequence Analysis, DNA/methods , X Chromosome Inactivation , Carrier Proteins/genetics , Cell Cycle Proteins/genetics , Chromosomal Proteins, Non-Histone/genetics , DEAD-box RNA Helicases/genetics , Exome , Female , Humans , Membrane Proteins , Methyl-CpG-Binding Protein 2/genetics , Nuclear Proteins/genetics
7.
Hum Mol Genet ; 24(25): 7171-81, 2015 Dec 20.
Article in English | MEDLINE | ID: mdl-26443594

ABSTRACT

Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected individuals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected individuals. We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.


Subject(s)
Antigens, Nuclear/genetics , Intellectual Disability/genetics , Cell Cycle Proteins , Chromosomes, Human, X/genetics , DNA Copy Number Variations/genetics , Humans , Male , Problem Behavior , Reverse Transcriptase Polymerase Chain Reaction
8.
Hum Genet ; 132(10): 1177-85, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23783460

ABSTRACT

Loss-of-function mutations in several different neuronal pathways have been related to intellectual disability (ID). Such mutations often are found on the X chromosome in males since they result in functional null alleles. So far, microdeletions at Xq24 reported in males always have been associated with a syndromic form of ID due to the loss of UBE2A. Here, we report on overlapping microdeletions at Xq24 that do not include UBE2A or affect its expression, in patients with non-syndromic ID plus some additional features from three unrelated families. The smallest region of overlap, confirmed by junction sequencing, harbors two members of the mitochondrial solute carrier family 25, SLC25A5 and SLC25A43. However, identification of an intragenic microdeletion including SLC25A43 but not SLC25A5 in a healthy boy excluded a role for SLC25A43 in cognition. Therefore, our findings point to SLC25A5 as a novel gene for non-syndromic ID. This highly conserved gene is expressed ubiquitously with high levels in cortex and hippocampus, and a presumed role in mitochondrial exchange of ADP/ATP. Our data indicate that SLC25A5 is involved in memory formation or establishment, which could add mitochondrial processes to the wide array of pathways that regulate normal cognitive functions.


Subject(s)
Adenine Nucleotide Translocator 2/metabolism , Chromosome Deletion , Chromosomes, Human, X/genetics , Intellectual Disability/genetics , Mitochondria/metabolism , Adenine Nucleotide Translocator 2/genetics , Alu Elements , Base Sequence , Brain/metabolism , Brain/pathology , Child, Preschool , Cohort Studies , DNA Mutational Analysis , Female , Heterozygote , Humans , Infant , Intellectual Disability/pathology , Male , Mitochondria/genetics , Molecular Sequence Data , Pedigree , X Chromosome Inactivation
9.
Eur J Med Genet ; 56(7): 379-82, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23721686

ABSTRACT

The advent of next-generation sequencing has proven to be a key force in the identification of new genes associated with intellectual disability. In this study, high-throughput sequencing of the coding regions of the X-chromosome led to the identification of a missense variant in the HUWE1 gene. The same variant has been reported before by Froyen et al. (2008). We compare the phenotypes and demonstrate that, in the present family, the HUWE1 mutation segregates with the more severe ID phenotypes of two out of three brothers. The third brother has a milder form of ID and does not carry the mutation.


Subject(s)
Chromosomes, Human, X/genetics , Intellectual Disability/genetics , Mutation, Missense , Phenotype , Ubiquitin-Protein Ligases/genetics , Child , Child, Preschool , Exome/genetics , Female , Humans , Intellectual Disability/diagnosis , Male , Pedigree , Tumor Suppressor Proteins , Upper Extremity Deformities, Congenital/diagnosis , Upper Extremity Deformities, Congenital/genetics
10.
Am J Hum Genet ; 91(6): 1122-7, 2012 Dec 07.
Article in English | MEDLINE | ID: mdl-23159249

ABSTRACT

We studied two unrelated boys with intellectual disability (ID) and a striking facial resemblance suggestive of a hitherto unappreciated syndrome. Exome sequencing in both families identified identical de novo mutations in PACS1, suggestive of causality. To support these genetic findings and to understand the pathomechanism of the mutation, we studied the protein in vitro and in vivo. Altered PACS1 forms cytoplasmic aggregates in vitro with concomitant increased protein stability and shows impaired binding to an isoform-specific variant of TRPV4, but not the full-length protein. Furthermore, consistent with the human pathology, expression of mutant PACS1 mRNA in zebrafish embryos induces craniofacial defects most likely in a dominant-negative fashion. This phenotype is driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells. Our findings suggest that PACS1 is necessary for the formation of craniofacial structures and that perturbation of its functions results in a specific syndromic ID phenotype.


Subject(s)
Intellectual Disability/genetics , Mutation , Neural Crest/metabolism , Vesicular Transport Proteins/genetics , Amino Acid Sequence , Animals , Base Sequence , Facies , Humans , Intellectual Disability/diagnosis , Male , Neural Crest/embryology , Syndrome , Zebrafish/embryology , Zebrafish/genetics , Zebrafish/metabolism
11.
J Med Genet ; 49(6): 366-72, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22636604

ABSTRACT

BACKGROUND: Deletions including chromosome 14 band q13 have been linked to variable phenotypes. With current molecular methods the authors aim to elucidate a genotype-phenotype correlation by accurately determining the size and location of the deletions and the associated phenotype. METHODS: Here the authors report the molecular karyotyping and phenotypic description of seven patients with overlapping deletions including chromosome 14q13. RESULTS: The authors show that deletions including 14q13 result in a recognisable phenotype mainly due to haploinsufficiency of two genes (NKX2-1, PAX9). FOXG1 (on chromosome band 14q12) involvement seems to be the main determinant of phenotype severity. The patients in this study without FOXG1 involvement and deletions of up to 10 Mb have a relatively mild phenotype. The authors cannot explain why some patients in literature with overlapping but smaller deletions appear to have a more severe phenotype. A previously presumed association with holoprosencephaly could not be confirmed as none of the patients in this series had holoprosencephaly. CONCLUSIONS: FOXG1 appears the main determinant of the severity of phenotypes resulting from deletions including 14q13. The collected data show no evidence for a locus for holoprosencephaly in the 14q13 region, but a locus for agenesis of the corpus callosum cannot be excluded.


Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 14 , Forkhead Transcription Factors/genetics , Holoprosencephaly/genetics , Nerve Tissue Proteins/genetics , Adult , Child , Chromosome Mapping , Female , Haploinsufficiency , Humans , Infant, Newborn , Karyotyping , Male , Nuclear Proteins/genetics , PAX9 Transcription Factor/genetics , Phenotype , Sequence Analysis, DNA , Thyroid Nuclear Factor 1 , Transcription Factors/genetics
12.
Am J Med Genet A ; 143A(18): 2160-4, 2007 Sep 15.
Article in English | MEDLINE | ID: mdl-17702016

ABSTRACT

Rubinstein-Taybi syndrome is a well-characterized genetic syndrome caused by haploinsufficiency of CBP in a majority of individuals. In 10% of cases a microdeletion in 16p13.3 affecting CBP is detected. We report on a patient with a de novo 345-480 kb micro-duplication the region, encompassing only CBP and TRAP1. This boy presented with various minor physical anomalies, moderate mental retardation, and an atrial septal defect, but none of the other typical characteristics of the Rubinstein-Taybi syndrome, such as the broad thumbs and first toes or facial characteristics. This finding implicates CBP as one of the causative genes for the trisomy 16p13 syndrome, and indicates this is a contiguous gene syndrome.


Subject(s)
CREB-Binding Protein/genetics , Gene Duplication , Heart Defects, Congenital/genetics , Intellectual Disability/genetics , Base Sequence , Chromosomes, Human, Pair 16 , DNA Primers , Humans , Infant , Male , Phenotype , Polymerase Chain Reaction , Syndrome , Trisomy
13.
Eur J Med Genet ; 48(2): 145-52, 2005.
Article in English | MEDLINE | ID: mdl-16053905

ABSTRACT

X-linked mental retardation (XLMR) is a heterogeneous disorder that can be classified as either non-specific (MRX), when mental retardation is the only feature, or as syndromic mental retardation (MRXS). Genetic defects underlying XLMR are being identified at a rapid pace, often starting from X-chromosomal aberrations and XLMR families with a well-defined linkage interval. Here, we present a new family with a syndromic form of XLMR, including mild mental retardation, short stature, microcephaly and hypogonadism. Two-point linkage analysis with 24 polymorphic markers spanning the entire X chromosome was carried out. We could assign the causative gene to a 6 cM interval in Xp22.1-p21.3, with a maximum LOD score of 2.61 for markers DXS989 and DXS1061 at theta = 0.00. No mutations were found in the presented family for two known MRX genes mapping to this interval, ARX and IL1RAPL-1. These data indicate that the interval Xp22.1-p21.3 contains at least one additional MRXS gene.


Subject(s)
Chromosomes, Human, X/genetics , Hypogonadism/genetics , Mental Retardation, X-Linked/genetics , Microcephaly/genetics , Adult , Belgium , Chromosome Mapping , Female , Growth Disorders/genetics , Humans , Infant, Newborn , Lod Score , Male , Middle Aged , Pedigree , Syndrome
14.
Ann Genet ; 45(1): 1-3, 2002.
Article in English | MEDLINE | ID: mdl-11934381

ABSTRACT

We report a female with Prader-Willi syndrome and hemihypertrophy. We discuss the possibility of an undetected mosaicism for trisomy 15 explaining this unusual feature.


Subject(s)
Chromosomes, Human, Pair 15 , Mosaicism , Prader-Willi Syndrome/physiopathology , Trisomy , Adult , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn
15.
Am J Med Genet ; 108(4): 310-4, 2002 Apr 01.
Article in English | MEDLINE | ID: mdl-11920836

ABSTRACT

In this report, we describe two siblings, a brother and a sister, with mental retardation and limb abnormalities (brachymetacarpy and brachymetatarsy in the brother and clinodactyly in his sister). Fluorescent in situ hybridization analysis (FISH) using subtelomeric probes proved that the patients carried an unbalanced subtelomeric rearrangement with 2qter deletion involving the Glypican 1 gene. Given the expression pattern in the developing limb bud, Glypican 1 gene represents a good candidate for brachydactyly E.


Subject(s)
Fingers/abnormalities , Genetic Predisposition to Disease/genetics , Heparan Sulfate Proteoglycans/genetics , Chromosome Deletion , Chromosomes, Human, Pair 2/genetics , Family Health , Female , Hand Deformities/complications , Hand Deformities/genetics , Humans , In Situ Hybridization, Fluorescence , Intellectual Disability/complications , Male , Middle Aged
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