Subject(s)
Cell-Free Nucleic Acids , Leukemia, Lymphocytic, Chronic, B-Cell , Adult , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Pregnancy , Pregnant Women , Prenatal Diagnosis , Trisomy/diagnosis , Trisomy/genetics , Trisomy 13 Syndrome , Trisomy 18 SyndromeABSTRACT
Constitutional heterozygous mutations in CHEK2 gene have been associated with hereditary cancer risk. To date, only a few homozygous CHEK2 mutations have been reported in families with cancer susceptibility. Here, we report two unrelated individuals with a personal and familial cancer history in whom biallelic CHEK2 alterations were identified. The first case resulted homozygous for the CHEK2 c.793-1 G > A (p.Asp265Thrfs*10) variant, and the second one was found to be compound heterozygous for the c.1100delC (p.Thr367Metfs*15) and the c.1312 G > T (p.Asp438Tyr) variants. Multiple cytogenetic anomalies were demonstrated on peripheral lymphocytes of both patients. A literature revision showed that a single other CHEK2 homozygous variant was previously associated to a constitutional randomly occurring multi-translocation karyotype from peripheral blood in humans. We hypothesize that, at least some biallelic CHEK2 mutations might be associated with a novel disorder, further expanding the group of chromosome instability syndromes. Additional studies on larger cohorts are needed to confirm if chromosomal instability could represent a marker for CHEK2 constitutionally mutated recessive genotypes, and to investigate the cancer risk and the occurrence of other anomalies typically observed in chromosome instability syndromes.
Subject(s)
Breast Neoplasms , Protein Serine-Threonine Kinases , Humans , Female , Protein Serine-Threonine Kinases/genetics , Genetic Predisposition to Disease , Checkpoint Kinase 2/genetics , Mutation , Genotype , Chromosomal InstabilityABSTRACT
About one child in 68 is affected by the autism spectrum disorder (ASD), one of the most common neurodevelopmental disorders linked to intellectual disability, especially in males, intellectual disability being diagnosable in about 60-70% of autistic individuals. The biological bases of ASD are not yet fully known, but they are generally considered multifactorial, although many genes and genomic loci have been proposed to be possibly associated with this condition. In this report, we describe the case of a 14-year-old female Italian proband affected by ASD, carrying a novel ~ 270 kb interstitial microduplication, localized at the distal portion of the 4q13.1 region. The rearrangement was inherited from a mild symptomatic father and included a large part of the single EPHA5 gene, a receptor tyrosine kinase involved in the neural development, already indicated to be linked to ASD by previous Genome Wide Association Studies. This imbalance represents, to the best of our knowledge, the smallest duplication identified to date that only impacts the EPHA5 gene. We hypothesize that the duplication of this gene may alter EPHA5 expression and that this may impact the autistic phenotype of the patient.
Subject(s)
Autism Spectrum Disorder/genetics , Receptor, EphA5/genetics , Adolescent , Autistic Disorder/genetics , Comparative Genomic Hybridization , Female , Gene Duplication/genetics , Genome-Wide Association Study , Genomics , Humans , Intellectual Disability/genetics , Italy , Phenotype , Receptor, EphA5/physiologyABSTRACT
XX true hermaphroditism, also know as ovotesticular disorder of sexual development (DSD), is a disorder of gonadal development characterized by the presence of both ovarian and testicular tissue in a 46,XX individual. The genetic basis for XX true hermaphroditism and sex reversal syndromes unrelated to SRY translocation is still mostly unclear. We report mutational analysis of the RSPO1 gene in a 46,XX woman with true hermaphroditism, palmoplantar keratoderma, congenital bilateral corneal opacities, onychodystrophy, and hearing impairment. R-spondin1 is a member of the R-spondin protein family and its pivotal role in sex determination has been recently described. We identified a homozygous splice-donor-site mutation in the RSPO1 gene in our patient. We found that the c.286+1G>A mutation led to an aberrantly spliced mRNA (r.95_286del), which is presumably translated into a partially functional protein (p.Ile32_Ile95del). Our case demonstrates for the first time, to our knowledge, that XX true hermaphroditism can be caused by a single gene mutation. The reported findings represent a further step toward a complete understanding of the complex mechanisms leading to DSDs.
Subject(s)
Homozygote , Mutation/genetics , Ovotesticular Disorders of Sex Development/genetics , Thrombospondins/genetics , Adult , Amino Acid Sequence , Base Sequence , DNA Mutational Analysis , Female , Gonads/cytology , Humans , Molecular Sequence Data , RNA Splicing , RNA, Messenger/genetics , RNA, Messenger/metabolism , Syndrome , Thrombospondins/chemistryABSTRACT
PURPOSE: PAX6 mutations cause aniridia as well as other various congenital eye abnormalities. Aniridia can be due to both point mutations and chromosomal deletions/rearrangements. Therefore, a complete search for PAX6 gene alterations in aniridia subjects requires a technically complex approach involving the comprehension of fluorescence in situ hybridization (FISH) analysis. In the present study, an Italian casistic of aniridia patients has been investigated and a quantitative polymerase chain reaction (PCR) assay to detect PAX6 gene deletions was set up. METHODS: Twenty-one aniridia patients were screened for point mutations (missense, nonsense, splicing-affecting, and short insertion/deletion) by using single-stranded conformational polymorphism (SSCP) and denaturing high performance liquid chromatography (dHPLC). To reveal deletions not detectable by SSCP or dHPLC, a quantitative PCR approach was set up for the PAX6 structural gene and for regions 5' and 3' to it at the level of WT1 and ELP4, respectively. RESULTS: Point mutations were found in 7 out of 21 patients. Three out of twenty-one patients showed deletions at the level of the PAX6 structural gene. In addition, two familial cases showed an undamaged PAX6 gene but a deletion in the region 3' to it at level of the ELP4 gene. In one of the families, the presence of the deletion has been confirmed by linkage analysis of polymorphic markers. CONCLUSIONS: In our casistic, a significant fraction of familial aniridia patients appears to be caused by a 3' deletion to PAX6, suggesting that evaluation of this alteration should be included in routine procedures of aniridia patients analysis. The quantitative PCR assay described here represents a simple approach to accomplish this task.
Subject(s)
Aniridia/genetics , Eye Proteins/genetics , Homeodomain Proteins/genetics , Paired Box Transcription Factors/genetics , Repressor Proteins/genetics , Sequence Deletion , Databases, Nucleic Acid , Female , Genetic Linkage , Genome, Human/genetics , Humans , Male , Nerve Tissue Proteins/genetics , PAX6 Transcription Factor , Pedigree , Point Mutation/genetics , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
X-linked intellectual disability accounts for 10-12% of cases of cognitive impairment in males. Mutations in IL1RAPL1 are an emerging form of apparently non-syndromic X-linked intellectual disability. We report a 8-year-old intellectually disabled boy with speech delay, and unusual facial and digital anomalies who showed a novel and complex IL1RAPL1 rearrangement. It was defined by two intragenic non-contiguous duplications inherited from the unaffected mother. Chromosome X inactivation study on the mother's blood leukocytes, urinary sediment and buccal swab did not show a significant skewed inactivation. Comparison with previously described patients with IL1RAPL1 disruption was carried. Although data on craniofacial features were scanty in many papers, subtle facial dysmorphism with a thin upper lip seemed a quietly represented picture without any other genotype-phenotype correlations. Our study expands the molecular repertoire of IL1RAPL1 mutations in intellectual disability and points out the need of more accurate clinical descriptions to better define the related phenotype.
Subject(s)
Face/abnormalities , Fingers/abnormalities , Intellectual Disability/genetics , Interleukin-1 Receptor Accessory Protein/genetics , Child , DNA/genetics , Gene Rearrangement , Genetic Diseases, X-Linked/genetics , Humans , Language Development Disorders/etiology , Language Development Disorders/genetics , Lip/abnormalities , Male , Toes/abnormalities , X Chromosome InactivationABSTRACT
The 3q27.3 microdeletion syndrome has been recently delineated in 7 subjects from 5 families sharing a 1.4 Mb smallest region of overlap. This condition appears recognizable by the association of Marfanoid habitus, mild but distinctive facial dysmorphism, intellectual disability, psychosis, and mood disorder. Here, we describe an additional 17-year-old man with an ~7.7-Mb deletion encompassing the 3q27.3 microdeletion critical region, previously run undetected at standard karyotyping. The constellation of major clinical findings overlaps with those reported in the 7 previously published patients and thus confirms the existence of a strongly recognizable syndrome linked to imbalance of 3q27.3. The role of AHSG and, possibly, of other genes in determining the 3q27.3 microdeletion habitus is discussed by comparison of the deleted segments. The involvement of adjacent loci and genes, such as OPA1 and GP5, may contribute in this patient to novel satellite features, such as optic atrophy and subclinical coagulopathy.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 3 , Adolescent , Humans , Male , Phenotype , SyndromeABSTRACT
Sex development is a process under genetic control directing both the bi-potential gonads to become either a testis or an ovary, and the consequent differentiation of internal ducts and external genitalia. This complex series of events can be altered by a large number of genetic and non-genetic factors. Disorders of sex development (DSD) are all the medical conditions characterized by an atypical chromosomal, gonadal, or phenotypical sex. Incomplete knowledge of the genetic mechanisms involved in sex development results in a low probability of determining the molecular definition of the genetic defect in many of the patients. In this study, we describe the clinical, cytogenetic, and molecular study of 88 cases with DSD, including 29 patients with 46,XY and disorders in androgen synthesis or action, 18 with 46,XX and disorders in androgen excess, 17 with 46,XY and disorders of gonadal (testicular) development, 11 classified as 46,XX other, eight with 46,XX and disorders of gonadal (ovarian) development, and five with sex chromosome anomalies. In total, we found a genetic variant in 56 out of 88 of them, leading to the clinical classification of every patient, and we outline the different steps required for a coherent genetic testing approach. In conclusion, our results highlight the fact that each category of DSD is related to a large number of different DNA alterations, thus requiring multiple genetic studies to achieve a precise etiological diagnosis for each patient.
ABSTRACT
BACKGROUND: Thrombocytopenia-absent radius syndrome is a rare autosomal recessive disorder characterized by megakaryocytic thrombocytopenia and longitudinal limb deficiencies mostly affecting the radial ray. Most patients are compound heterozygotes for a 200 kb interstitial microdeletion in 1q21.1 and a hypomorphic allele in RBM8A, mapping in the deleted segment. At the moment, the complete molecular characterization of thrombocytopenia-absent radius syndrome is limited to a handful of patients mostly ascertained in the pediatric age CASE PRESENTATION: We report on a fetus with bilateral upper limb deficiency found at standard prenatal ultrasound examination. The fetus had bilateral radial agenesis and humeral hypo/aplasia with intact thumbs, micrognathia and urinary anomalies, indicating thrombocytopenia-absent radius syndrome. Molecular studies demonstrated compound heterozygosity for the 1q21.1 microdeletion and the RBM8A rs139428292 variant at the hemizygous state, inherited from the mother and father, respectively CONCLUSION: The molecular information allowed prenatal diagnosis in the following pregnancy resulting in the birth of a healthy carrier female. A review was carried out with the attempt to the trace the fetal ultrasound presentation of thrombocytopenia-absent radius syndrome and discussing opportunities for second-tier molecular studies within a multidisciplinary setting.
Subject(s)
Abnormalities, Multiple/genetics , Alleles , Fetus/pathology , Heterozygote , Megalencephaly/genetics , Prenatal Diagnosis , RNA-Binding Proteins/genetics , Thrombocytopenia/genetics , Upper Extremity Deformities, Congenital/genetics , Abnormalities, Multiple/diagnostic imaging , Abnormalities, Multiple/pathology , Adult , Autopsy , Chromosome Deletion , Chromosomes, Human, Pair 1/diagnostic imaging , Chromosomes, Human, Pair 1/genetics , Comparative Genomic Hybridization , Congenital Bone Marrow Failure Syndromes , Fatal Outcome , Female , Fetus/metabolism , Humans , Male , Megalencephaly/diagnostic imaging , Megalencephaly/pathology , Pedigree , Pregnancy , Radiography , Radius/diagnostic imaging , Radius/pathology , Syndrome , Thrombocytopenia/diagnostic imaging , Thrombocytopenia/pathology , Upper Extremity Deformities, Congenital/diagnostic imaging , Upper Extremity Deformities, Congenital/pathologyABSTRACT
Strømme syndrome is a rare multiple congenital malformation syndrome consisting in apple peel intestinal atresia, ocular anomalies, microcephaly and developmental delay. To date, this condition was described in a couple of sibs and 7 additional sporadic patients. We report on a 11-month-old female, who requested surgical correction for jejunal atresia shortly after birth and also presented with megalocornea and persistence of the pupillary membrane. Microcephaly and developmental delay were absent at last examination. An oligonucleotide CGH-array analysis excluded cryptic chromosome rearrangement(s). Comparison of the previously published and present patients added some details on the natural history of Strømme syndrome. Delivery is usually performed preterm possibly due to polyhydramnios. Birth parameters, especially head circumference, are commonly at the lower end of the normal range. Microcephaly is more frequently but not constantly observed in older individuals, thus suggesting a progressive course, and may relate to an underlying neuronal migration defect. Jejunal atresia has an apple peel appearance in most but not all patients and its post-surgical course is usually uneventful. The ocular phenotype comprises a wide range of anterior chamber anomalies with sclerocornea/corneal leukoma being the most common.
Subject(s)
Eye Abnormalities/physiopathology , Intestinal Atresia/complications , Abnormalities, Multiple/diagnosis , Comparative Genomic Hybridization , Developmental Disabilities/diagnosis , Eye/pathology , Female , Humans , Infant , Microcephaly/diagnosis , SyndromeABSTRACT
Anophthalmia/microphthalmia is a rare developmental craniofacial defect, which recognizes a wide range of causes, including chromosomal abnormalities, single-gene mutations as well as environmental factors. Heterozygous mutations in the SOX2 gene are the most common monogenic form of anophthalmia/microphthalmia, as they are reported in up to 10-15% cases. Here, we describe a sporadic patient showing bilateral anophthalmia/microphthalmia and micropenis caused by a novel mutation (c.59_60insGG) in the SOX2 gene. Morphological and endocrinological evaluations excluded any anomaly of the hypothalamus-pituitary axis. Our finding supports the hypothesis that SOX2 is particularly prone to slipped-strand mispairing, which results in a high frequency of point deletions/insertions.