ABSTRACT
Facioscapulohumeral dystrophy (FSHD) is associated with somatic chromatin relaxation of the D4Z4 repeat array and derepression of the D4Z4-encoded DUX4 retrogene coding for a germline transcription factor. Somatic DUX4 derepression is caused either by a 1-10 unit repeat-array contraction (FSHD1) or by mutations in SMCHD1, which encodes a chromatin repressor that binds to D4Z4 (FSHD2). Here, we show that heterozygous mutations in DNA methyltransferase 3B (DNMT3B) are a likely cause of D4Z4 derepression associated with low levels of DUX4 expression from the D4Z4 repeat and increased penetrance of FSHD. Recessive mutations in DNMT3B were previously shown to cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. This study suggests that transcription of DUX4 in somatic cells is modified by variations in its epigenetic state and provides a basis for understanding the reduced penetrance of FSHD within families.
Subject(s)
DNA (Cytosine-5-)-Methyltransferases/genetics , Epigenetic Repression/genetics , Muscular Dystrophy, Facioscapulohumeral/genetics , Mutation/genetics , Penetrance , Tandem Repeat Sequences/genetics , Adolescent , Adult , Aged , Amino Acid Sequence , Child , Child, Preschool , Chromatin/genetics , DNA (Cytosine-5-)-Methyltransferases/chemistry , DNA Methylation , Female , Humans , Infant , Male , Middle Aged , Pedigree , Protein Conformation , Sequence Homology, Amino Acid , DNA Methyltransferase 3BABSTRACT
Copy number variations (CNVs) on the short arm of chromosome 19 are relatively rare. We present a patient with a tandem de novo 3.9 Mb duplication of 19p13.12p13.2 and an adjacent 288 kb deletion of 19p13.12. The CNVs were detected by genome wide SNP-array and confirmed by fluorescence in situ hybridization. Mate-pair sequencing revealed two breakpoint junctions leading to a germline tandem inverted duplication and an adjacent deletion. The patient had a major congenital heart defect and refractory edema leading to metabolic and endocrinological disturbances. Further complications occurred due to refractory chylothorax, severe inflammatory response syndrome, and repeating sepsis. After 2 months, the child died due to intractable respiratory failure. The phenotype of this patient was compared with reported patients with overlapping deletions or duplications. We conclude that the congenital heart defect, respiratory insufficiency, and abnormal neurologic examination are most likely due the contiguous gene deletion/duplication.
Subject(s)
Chromosome Deletion , Chromosome Duplication , Chromosomes, Human, Pair 19 , Humans , Infant, Newborn , MaleABSTRACT
Heterozygous mutations in PMS2 are involved in Lynch syndrome, whereas biallelic mutations are found in Constitutional mismatch repair-deficiency syndrome patients. Mutation detection is complicated by the occurrence of sequence exchange events between the duplicated regions of PMS2 and PMS2CL. We investigated the frequency of such events with a nonspecific polymerase chain reaction (PCR) strategy, co-amplifying both PMS2 and PMS2CL sequences. This allowed us to score ratios between gene and pseudogene-specific nucleotides at 29 PSV sites from exon 11 to the end of the gene. We found sequence transfer at all investigated PSVs from intron 12 to the 3' end of the gene in 4 to 52% of DNA samples. Overall, sequence exchange between PMS2 and PMS2CL was observed in 69% (83/120) of individuals. We demonstrate that mutation scanning with PMS2-specific PCR primers and MLPA probes, designed on PSVs, in the 3' duplicated region is unreliable, and present an RNA-based mutation detection strategy to improve reliability. Using this strategy, we found 19 different putative pathogenic PMS2 mutations. Four of these (21%) are lying in the region with frequent sequence transfer and are missed or called incorrectly as homozygous with several PSV-based mutation detection methods.
Subject(s)
Adenosine Triphosphatases/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Repair Enzymes/genetics , DNA-Binding Proteins/genetics , Polymerase Chain Reaction/methods , Case-Control Studies , Humans , Mismatch Repair Endonuclease PMS2 , Mutation , Pseudogenes/geneticsABSTRACT
Ring chromosomes are rare cytogenetic findings and are associated at phenotypic level with mental retardation and congenital abnormalities. Features specific for ring chromosome syndromes often overlap with the features of terminal deletions for the corresponding chromosomes. Here, we report a case of a ring chromosome 14 which was identified by conventional cytogenetics and shown to have a terminal deletion and an additional inverted duplication with a triplication by using large insert clone and oligo array-comparative genomic hybridization (array-CGH), fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA). The combination of an inverted duplication with a terminal deletion in a ring chromosome is of special interest for the described syndromes of chromosome 14. The presented findings might explain partly overlapping clinical features described in terminal deletion, duplication and ring chromosome 14 cases, as these rearrangements can be easily overlooked when performing GTG-banding only. Furthermore, we suggest that ring chromosome formation can act as an alternative chromosome rescue next to telomere healing and capture, particularly for acrocentric chromosomes. To our knowledge, this is the first time an inverted duplication with a terminal deletion in a ring chromosome is identified and characterized using high-resolution molecular karyotyping. Systematic evaluation of ring chromosomes by array-CGH might be especially useful in distinguishing cases with a duplication/deletion from those with a deletion only.
Subject(s)
Abnormalities, Multiple/diagnosis , Chromosome Aberrations , Chromosomes, Human, Pair 14/genetics , Intellectual Disability/diagnosis , Oligonucleotide Array Sequence Analysis/methods , Ring Chromosomes , Abnormalities, Multiple/genetics , Child , Female , Gene Duplication , Humans , In Situ Hybridization, Fluorescence , Intellectual Disability/genetics , Sequence DeletionABSTRACT
Ring chromosomes are uncommon cytogenetic findings and are often associated with clinical features overlapping the phenotype of patients with terminal deletions of the corresponding chromosome. Most of the ring chromosomes arise sporadically and parental transmission is rarely observed. We report five patients carrying a ring chromosome 11, with three of the patients belonging to the same family. SNP array analysis was performed to characterize the different ring chromosomes and the clinical phenotypes were compared with previously reported patients with ring chromosome 11.
Subject(s)
Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Chromosomes, Human, Pair 11 , Ring Chromosomes , Adolescent , Adult , Child , Child, Preschool , Chromosome Deletion , Comparative Genomic Hybridization , Facies , Female , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Male , Polymorphism, Single Nucleotide , Young AdultABSTRACT
The most common mutations found in FBN1 are missense mutations (56%), mainly substituting or creating a cysteine in a cbEGF domain. Other mutations are frameshift, splice and nonsense mutations. There are only a few reports of patients with marfanoid features and a molecularly proven complete deletion of a FBN1 allele. We describe the clinical features of 10 patients with a complete FBN1 gene deletion. Seven patients fulfilled the Ghent criteria for Marfan syndrome (MFS). The other three patients were examined at a young age and did not (yet) present the full clinical picture of MFS yet. Ectopia lentis was present in at least two patients. Aortic root dilatation was present in 6 of the 10 patients. In three patients, the aortic root diameter was on the 95th percentile and in one patient, the diameter of the aortic root was normal, the cross-section, however, had a cloverleaf appearance. Two patients underwent aortic root surgery at a relatively young age (27 and 34 years). Mitral valve prolapse was present in 4 of the 10 patients, and billowing of the mitral valve in 1. All patients had facial and skeletal features of MFS. Two patients with a large deletion extending beyond the FBN1 gene had an extended phenotype. We conclude that complete loss of one FBN1 allele does not predict a mild phenotype, and these findings support the hypothesis that true haploinsufficiency can lead to the classical phenotype of Marfan syndrome.
Subject(s)
Alleles , Marfan Syndrome/genetics , Microfilament Proteins/genetics , Mutation , Adolescent , Adult , Child , Child, Preschool , Cysteine/metabolism , Ectopia Lentis/genetics , Ectopia Lentis/pathology , Female , Fibrillin-1 , Fibrillins , Haploinsufficiency , Humans , Male , Mitral Valve Prolapse/genetics , Phenotype , Sequence Deletion , Young AdultABSTRACT
OBJECTIVE: To evaluate to what extent couples carrying a balanced structural chromosome abnormality follow up the advice to opt for invasive prenatal diagnosis (PND) in subsequent pregnancies. DESIGN: Index-control study. SETTING: Six centers for Clinical Genetics in The Netherlands. PATIENT(S): Couples referred for chromosome analysis after recurrent miscarriage between 1992 and 2001 and with at least one pregnancy after disclosure; 239 carrier couples and 389 noncarrier couples. INTERVENTION(S): Questionnaire, medical record checking. MAIN OUTCOME MEASURE(S): Uptake of invasive PND. RESULT(S): Only 53 of 239 (22%) carrier couples underwent a PND procedure (CVS or amniocentesis) in all subsequent pregnancies. A relatively high number, 105 (44%) carrier couples, refrained from PND in all subsequent pregnancies. More carrier couples with maternal age >or=36 years (20/33 = 61%) refrained from PND, compared with carrier couples with maternal age <36 years (85/206 = 41%). In women >or=36 years, an equal proportion of carrier and noncarrier couples refrained from PND (61% vs. 54%). CONCLUSION(S): The advice to opt for invasive PND in carrier couples is poorly followed, especially in carrier couples with maternal age >or=36 years. The motivations of carrier couples to opt for or refrain from invasive PND procedures should be the topic for further research to optimize clinical care and informative decision making.
Subject(s)
Abortion, Habitual/diagnosis , Abortion, Habitual/genetics , Chromosome Aberrations , Heterozygote , Prenatal Diagnosis/trends , Adult , Chromosome Disorders/diagnosis , Chromosome Disorders/genetics , Chromosome Disorders/prevention & control , Female , Follow-Up Studies , Genetic Carrier Screening/methods , Humans , Male , Pregnancy , Prenatal Diagnosis/methodsABSTRACT
OBJECTIVE: To report a case of a 46,XX male with an insertion of the sex-determining region Y (SRY) region in the terminal end of the long arm of chromosome 16. DESIGN: Case report. SETTING: Molecular and cytogenetic units in a university hospital. PATIENT(S): An infertile male, with normal masculinization of the external genitalia, who was referred for chromosomal analysis as an unaffected member of a family with idiopathic hypertrophic osteoarthropathy. INTERVENTION(S): Cytogenetic investigation, physical examination, and hormonal assays. MAIN OUTCOME MEASURE(S): Chromosomal analysis using GTG banding and fluorescence in situ hybridization (FISH). RESULT(S): Conventional chromosome analysis revealed a normal 46,XX karyotype. The FISH with bacterial artificial chromosomes (BACs) of the SRY region indicated the presence of this region on the terminal end of the long arm of chromosome 16. CONCLUSION(S): This is the first case of a 46,XX male with the SRY gene present on an autosome-here chromosome 16. The size of the inserted region containing SRY, inserted in 16qter, is approximately 600 kb.
Subject(s)
Chromosomes, Human, Pair 16/genetics , DNA Transposable Elements , Gonadal Dysgenesis, 46,XX/genetics , Sex-Determining Region Y Protein/genetics , Chromosome Mapping , Chromosomes, Artificial, Bacterial , Cytogenetic Analysis , Gonadal Dysgenesis, 46,XX/complications , Humans , In Situ Hybridization, Fluorescence , Infertility, Male/etiology , Male , Middle AgedABSTRACT
OBJECTIVE: To identify additional factors, such as maternal age or factors related to previous reproductive outcome or family history, and the corresponding probability of carrying a chromosome abnormality in couples with two or more miscarriages. DESIGN: Nested case-control study. SETTING: Six centres for clinical genetics in the Netherlands. PARTICIPANTS: Couples referred for chromosome analysis after two or more miscarriages in 1992-2000; 279 carrier couples were marked as cases, and 428 non-carrier couples served as controls. MAIN OUTCOME MEASURES: Independent factors influencing the probability of carrier status and the corresponding probability of carrier status. RESULTS: Four factors influencing the probability of carrier status could be identified: maternal age at second miscarriage, a history of three or more miscarriages, a history of two or more miscarriages in a brother or sister of either partner, and a history of two or more miscarriages in the parents of either partner. The calculated probability of carrier status in couples referred for chromosome analysis after two or more miscarriages varied between 0.5% and 10.2%. CONCLUSIONS: The probability of carrier status in couples with two or more miscarriages is modified by additional factors. Selective chromosome analysis would result in a more appropriate referral policy, could decrease the annual number of chromosome analyses, and could therefore lower the costs.