ABSTRACT
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Subject(s)
Humans , Male , Infant, Newborn , Diaphragm/abnormalities , Heart Defects, Congenital/complications , Pulmonary Artery/abnormalities , Hernia, Umbilical/complications , Dextrocardia/complications , Gonads/abnormalitiesABSTRACT
Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.
Subject(s)
Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , DNA-Binding Proteins/genetics , Face/abnormalities , Genetic Association Studies , Hematologic Diseases/diagnosis , Hematologic Diseases/genetics , Mutation , Neoplasm Proteins/genetics , Vestibular Diseases/diagnosis , Vestibular Diseases/genetics , Facies , Female , Humans , Male , Phenotype , Sequence Analysis, DNAABSTRACT
BACKGROUND: Conradi-Hünermann-Happle syndrome (CDPX2, OMIM 302960) is an inherited X-linked dominant variant of chondrodysplasia punctata which primarily affects the skin, bones and eyes. CDPX2 results from mutations in EBP (emopamil binding protein), and presents with increased levels of sterol precursors 8(9)-cholesterol and 8-dehydrocholesterol. OBJECTIVES: To expand the understanding of CDPX2, clinically, biochemically and genetically. METHODS: We present one of the largest series reported to date, including 13 female patients belonging to nine Spanish families. Patients were studied biochemically using gas chromatography-mass spectrometry, genetically using polymerase chain reaction and in their methylation status using the HUMARA assay. RESULTS: In our cases, there was a clear relationship between abnormal sterol profile and the EBP gene mutation. We describe three novel mutations in the EBP gene. EBP mutations were inherited in three out of nine families and were sporadic in the remaining cases. CONCLUSIONS: No clear genotype-phenotype correlation was found. Patients' biochemical profiles did not reveal a relationship between sterol profiles and severity of disease. A skewed X-chromosome inactivation may explain the clinical phenotype in CDPX2 in some familial cases.
Subject(s)
Chondrodysplasia Punctata/genetics , Genetic Diseases, X-Linked/genetics , Mutation/genetics , Steroid Isomerases/genetics , X Chromosome Inactivation/genetics , Adult , Cholestadienols/metabolism , Cholesterol/metabolism , Chondrodysplasia Punctata/metabolism , DNA Mutational Analysis/methods , Female , Genetic Diseases, X-Linked/metabolism , Genotype , Humans , Infant , Phenotype , SpainABSTRACT
BACKGROUND: Androgen receptor (AR) gene mutations are the most frequent cause of 46,XY disorders of sex development (DSD) and are associated with a variety of phenotypes, ranging from phenotypic women [complete androgen insensitivity syndrome (CAIS)] to milder degrees of undervirilization (partial form or PAIS) or men with only infertility (mild form or MAIS). OBJECTIVE: The aim of the study was to characterize the contribution of the AR gene to the molecular cause of 46,XY DSD in a series of Spanish patients. SETTING: We studied a series of 133 index patients with 46,XY DSD in whom gonads were differentiated as testes, with phenotypes including varying degrees of undervirilization, and in whom the AR gene was the first candidate for a molecular analysis. METHODS: The AR gene was sequenced (exons 1 to 8 with intronic flanking regions) in all patients and in family members of 61% of AR-mutated gene patients. RESULTS: AR gene mutations were found in 59 individuals (44.4% of index patients), of whom 46 (78%) were CAIS and 13 (22%) PAIS. Fifty-seven different mutations were found: 21.0% located in exon 1, 15.8% in exons 2 and 3, 57.9% in exons 4-8, and 5.3% intronic. Twenty-three mutations (40.4%) had been previously described and 34 (59.6%) were novel. CONCLUSIONS: AR gene mutation is the most frequent cause of 46,XY DSD, with a clearly higher frequency in the complete phenotype. Mutations spread along the whole coding sequence, including exon 1. This series shows that 60% of mutations detected during the period 2002-2009 were novel.
Subject(s)
Gonadal Dysgenesis, 46,XY/genetics , Receptors, Androgen/genetics , 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics , Adolescent , Child , Child, Preschool , Exons/genetics , Female , Fibroblasts/metabolism , Gonadal Dysgenesis, 46,XY/pathology , Heterozygote , Humans , Infant , Introns/genetics , Male , Mutation/genetics , Mutation/physiology , Phenotype , Receptors, Androgen/blood , Reverse Transcriptase Polymerase Chain Reaction , Sexual Behavior , Testis/pathologyABSTRACT
La trisomía 16 es la aneuploidia más frecuente en los abortosespontáneos de primer trimestre, siendo incompatible conla vida. Sin embargo, de forma infrecuente han sido descritosrecién nacidos con aneuploidias parciales de este cromosoma.Presentamos el segundo caso diagnosticado prenatalmentede trisomía total del brazo largo del cromosoma 16.El feto era portador de una dotación cromosómica desequilibrada46 XY, der(14) t (14;16) (p10;q10) como consecuenciade una translocación materna (AU)
Full trisomy is the most frequent first trimester spontaneousmiscarriages chromosome aneuploidy, being incompatiblewith life. However, partial aneuploidies of this chromosomehave been uncommonly reported in newborns.We present the second prenatal diagnosis of chromosome16 long arm trisomy. The fetus was found to have an abnormalkaryotype of 46 XY, der (14) t (14;16) (p10;q10) inheritedfrom a maternal translocation (AU)
Subject(s)
Humans , Female , Pregnancy , Chromosomes, Human, Pair 16 , Prenatal Diagnosis , Trisomy/diagnosisABSTRACT
Tetrasomy of short arm of chromosome 9 constitutes a clinically recognizable chromosomal syndrome. Isochromosome 9p shows a strong propensity to tissue-limited mosaicism. It occurs predominantly in peripheral blood cultures, often at a lower frequency or even absent in skin, amniotic fluid or chorionic villous cell cultures. Tissue-limited nature of mosaicism may render prenatal detection of this condition very difficult. Herein, we report two new cases of mosaic tetrasomy 9p. Conventional cytogenetics (CC) and FISH studies demonstrated a differential expression of the mosaicism in several tissues. We review the literature and discuss the implications of these findings in cytogenetic prenatal diagnosis.
Subject(s)
Aneuploidy , Chromosome Disorders/diagnosis , Chromosomes, Human, Pair 9 , Mosaicism/genetics , Child, Preschool , Chromosome Disorders/genetics , Cytogenetic Analysis , Female , Humans , In Situ Hybridization, Fluorescence , Isochromosomes/genetics , Male , Mosaicism/pathology , Prenatal Diagnosis , SyndromeSubject(s)
Aneuploidy , Centromere/genetics , Chromosome Aberrations , Adult , Fatal Outcome , Female , Fetal Death , Humans , Karyotyping , Pregnancy , Prenatal Diagnosis , SyndromeABSTRACT
We present three patients with variegated aneuploidy and premature centromere division (PCD), a rare chromosomal abnormality in humans. Comparison of these three and eight other patients with variegated aneuploidy related to PCD demonstrates a phenotype comprising most frequently microcephaly, CNS anomalies (with cerebellar affection and migration defects), mental retardation, pre-and postnatal growth retardation, flat and broad nasal bridge, apparently low-set ears, eye and skin abnormalities, and ambiguous genitalia in male patients. The occurrence of Wilms tumor in three patients, rhabdomyosarcoma in two others and acute leukemia in a fifth characterizes this condition as a chromosome or genome instability disorder with a high risk of malignancy. FISH studies in uncultured blood and buccal smear cells demonstrate that the random aneuploidies are not limited to cultured cells, but also occur in vivo.
Subject(s)
Aneuploidy , Centromere/genetics , Neoplasms/genetics , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Adult , Child , Cytogenetic Analysis , Female , Genetic Predisposition to Disease , Humans , Infant , Intellectual Disability/complications , Intellectual Disability/genetics , Male , Microcephaly/complications , Microcephaly/genetics , Neoplasms/etiologyABSTRACT
Cytogenetic analysis, fluorescent in situ hybridisation (FISH), and molecular amplification have been used to characterise the transfer of Yp fragments to Xp22.3 in six XX males. PCR amplification of the genes SRY, RPS4Y, ZFY, AMELY, KALY, and DAZ and of several other markers along the Y chromosome short and long arms indicated the presence of two different breakpoints in the Y fragment. However, the clinical features were very similar in five of the cases, showing a male phenotype with small testes, testicular atrophy, and azoospermia. All these patients have normal intelligence and a stature within the normal male range. In the remaining case, the diagnosis was made prenatally in a fetus with male genitalia detected by ultrasound and a 46,XX karyotype in amniocytes and fetal blood. Molecular analysis of fetal DNA showed the presence of the SRY gene. FISH techniques also showed Y chromosomal DNA on Xp22.3 in metaphases of placental cells. To our knowledge, this is the second molecular prenatal diagnosis reported of an XX male.
Subject(s)
Disorders of Sex Development , Nuclear Proteins , Sex Chromosome Aberrations/genetics , Transcription Factors , Translocation, Genetic , Y Chromosome/genetics , DNA-Binding Proteins/genetics , Female , Humans , Hypogonadism , In Situ Hybridization, Fluorescence , Karyotyping , Male , Oligospermia/genetics , Prenatal Diagnosis , Sex Chromosome Aberrations/diagnosis , Sex-Determining Region Y Protein , X Chromosome/geneticsABSTRACT
We report an 18-week-old fetus with at 47, XY, -12, +12q, +psu idic(12p) karyotype, mild dysmorphic features and absence of the brachiocephalic truncus.
Subject(s)
Abnormalities, Multiple/genetics , Brachiocephalic Trunk/embryology , Chromosome Aberrations/genetics , Chromosomes, Human, Pair 12/ultrastructure , Fetal Diseases/genetics , Trisomy , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/embryology , Abnormalities, Multiple/pathology , Abortion, Induced , Adult , Amniocentesis , Chromosome Aberrations/diagnosis , Chromosome Aberrations/embryology , Chromosome Aberrations/pathology , Chromosome Disorders , Chromosomes, Human, Pair 12/genetics , Face/embryology , Face/pathology , Female , Fetal Diseases/diagnosis , Fetal Diseases/pathology , Fetus/pathology , Gestational Age , Humans , Karyotyping , PregnancyABSTRACT
We report an anencephalic fetus with acrania, cervicodorsal rachischisis, and a 46,X,del(X)(p22.1) karyotype. Necropsy revealed a left diaphragmatic hernia, ipsilateral lung hypoplasia, and intestinal malrotation. The fetus also had horseshoe kidneys and adrenal gland hypoplasia with absence of the fetal zone.
Subject(s)
Anencephaly/genetics , Gene Deletion , Sex Chromosome Aberrations , X Chromosome , Adrenal Glands/pathology , Adult , Female , Humans , Intestines/abnormalities , Kidney/abnormalities , Lung/pathology , Pregnancy , Sex Chromosome Aberrations/pathology , Skull/abnormalitiesABSTRACT
The authors report the case of a girl with psychomotor and growth retardation, ventricular septal defect, patent ductus arteriosus, bulging forehead, prominent philtrum, low nasal bridge, inner epicanthal folds, strabismus, miosis, low set ears with prominence of antihelices, short neck, single transverse crease and camptodactyly of the fourth finger in both hands. G-banded chromosomal analysis revealed a 46, XX, del (6) (p23) chromosome constitution. A review of the phenotypes of the patients known with this chromosome deletion is presented.