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Why Chromosomes Are Relevant
Abstracts 4p12. Genes within this region include members of the GABA-A receptor gene family, which have been implicated in the etiology of autism and susceptibility to alcohol dependence, and may in tern play a role in the family’s problems with drugs and alcohol. The maternal great grandmother (I.1) did not have the duplications of 16q observed on array in the other family members. However, she was found to have a 461 kb loss on 16q21. This appears to be the same region which separates two of the duplicated regions observed in other family members. FISH analysis has determined the chromosome 16 duplicated regions have been inserted into the short arm of chromosome 4. Further molecular characterization of the duplication, deletions, and insertion are needed for a better understanding of the genomic architecture and mechanism of this complex rearrangement of chromosome 16. The complex rearrangement and copy number aberrations observed in the majority of this family appear to have begun as a unique deletion on chromosome 4p and a unique deletion of chromosome 16q21 in generation I as revealed by microarray analysis. Since at least two of her children received the insertion duplication, she most likely has a balanced version of the insertion. The complex duplication is speculated to have emerged by either nonhomologous end joining recombination (NHEJ) such as in a chromothripsis type event or non-allelic homologous recombination (NAHR) due to microhomology. NAHR mediated by regions of sequence homology at the breakpoints of the 4p deletion and the proximal and distal breakpoints of chromosome 16 segments might best explain the insertion of the 16 into chromosome 4. Further molecular characterization of the breakpoints involved will help elucidate the mechanism which produced this complex aberration.
25 A Rare Case of Russell-Silver and 1p36 Deletion Syndromes Donna Blackwell, Shannon Gaskin, Trisha Marsh, Yassmine Akkari
A peripheral blood sample was received from a 5 month old male for chromosomal microarray testing. Prenatally, there was evidence of IUGR and oligohydramnios and was delivered at 36 weeks gestation. At his exam at 5 months, he was found to be below the third percentile in all of his growth parameters. After numerous visits to a nutritional consult, he had not caught up in weight or growth. In addition to this failure to thrive, he showed hypotonia and developmental delay. Dysmorphic features were noted with low set ears, down slanting palpebral fissures, and a triangular face with prominent forehead and narrow chin. There was significant clinodactyly and the possibility of Russell-Silver syndrome was raised. Chromosome microarray studies revealed arr[hg19] 1p36.33p36.32(746,608-2,577,794)x1, 11p15.5p15.4(196,966-3,026,601)x3, establishing the diagnosis of both Russell-Silver and 1p36 syndromes. In this study, we present the clinical features of both syndromes and their mechanism and discuss the follow-up for this patient and his family.
26 Why Chromosomes Are Relevant Athena M. Cherry, Jesse M. Williams, Jr, Yuen Cho, Rong Luo, Dana Freebury, Charles D. Bangs
237 With the recommendation that chromosomal microarrays be used as a first tier test prenatally, in cases with ultrasound abnormalities, and postnatally, and the looming specter of next generation sequencing (NGS) for copy number changes, the value of routine chromosome analysis is often forgotten. Here we report two examples of important chromosome abnormalities that would have been missed if microarray had been performed without the benefit of karyotypic analysis. The first case is an amniotic fluid study performed on a 29 year old G3P2 woman at 16 weeks 4 days gestation due to a cystic hygroma and a heart defect. Fourteen of 15 in situ colonies had apparently normal 46,XX chromosomes. One whole colony had trisomy 17. This was the seventh colony examined. An additional 12 colonies from three different coverslips were screened for trisomy 17 and one additional trisomy 17 colony was observed. While mosaicism for trisomy 17 is relatively rare, the phenotype can include growth retardation, cardiac anomalies and minor dysmorphic features. The patient was counseled about these risks, but decided to continue. At birth, the cardiac defect was determined to be a ventricular septal defect with a supramitral ring and patent ductus arteriosus. At 2 days of age, a peripheral blood karyotype was performed and showed a normal 46,XX karyotype in all 50 cells examined. This was not unexpected, as cases reported in the literature show confinement of the trisomy 17 cells to fibroblasts. At 17 months of age, the patient showed failure to thrive and developmental delay. During cardiac surgery, skin fibroblasts and subaortic membrane were obtained for chromosome analysis. Four of 20 metaphases examined showed trisomy 17. Had this mother not had prenatal chromosome analysis, this lowlevel (7.4%) mosaicism would have been missed by microarray. As well, performing a limited chromosome analysis of 5 metaphases would have also missed this anomaly. Mosaic trisomy 17 limited to fibroblasts would also never have been suspected in a child with developmental delay and a heart defect. This child would most likely never have a diagnosis. The second case is a blood chromosome analysis performed on a newborn with ambiguous genitalia. Noninvasive prenatal screening (NIPS) had predicted an XX sex chromosome complement. At birth, the infant was small for gestational age and had ambiguous genitalia with fused, rugated labia. A mass was palpated in the right inguinal area. Sex was unassigned with the differential of enlarged clitoris vs. microphallus with penoscrotal hypospadias. STAT chromosomes and SRY FISH were ordered. The first 10 metaphases examined from a 48 hour culture were 45,X. The remaining 10 metaphases showed four cells with what appeared to be an isodicentric of the short arm of the Y chromosome [idic(Y)]. Interphase FISH was positive for SRY in 9 of 100 interphase nuclei examined, while metaphase FISH showed the SRY signal on the idic(Y). Interphase FISH for the X and Y chromosomes showed 146 (73%) with only an X chromosome signal, 28 (14%) with one X and one Y signal, 20 (10%) with one X and three Y signals and 6 (3%) with one X and two Y signals. Individuals with 45,X/46,X,idic(Y) have a wide range of phenotypes from Turner syndrome to normal male with spermatogenic failure. This spectrum can include mixed gonadal dysgenesis and ambiguous genitalia. Interestingly, at 8 months this child was found to have a right undescended testis, a left streak gonad, and a left unicornate uterus, cervix and vagina. The parents have decided to raise him as male. He has had some increase in virilization. Again, it is doubtful that a microarray would have detected this idic(Y). This re-emphasizes that particularly in disorders of sexual differentiation, chromosome analysis is an important first step.
25 A Rare Case of Russell-Silver and 1p36 Deletion Syndromes Donna Blackwell, Shannon Gaskin, Trisha Marsh, Yassmine Akkari
A peripheral blood sample was received from a 5 month old male for chromosomal microarray testing. Prenatally, there was evidence of IUGR and oligohydramnios and was delivered at 36 weeks gestation. At his exam at 5 months, he was found to be below the third percentile in all of his growth parameters. After numerous visits to a nutritional consult, he had not caught up in weight or growth. In addition to this failure to thrive, he showed hypotonia and developmental delay. Dysmorphic features were noted with low set ears, down slanting palpebral fissures, and a triangular face with prominent forehead and narrow chin. There was significant clinodactyly and the possibility of Russell-Silver syndrome was raised. Chromosome microarray studies revealed arr[hg19] 1p36.33p36.32(746,608-2,577,794)x1, 11p15.5p15.4(196,966-3,026,601)x3, establishing the diagnosis of both Russell-Silver and 1p36 syndromes. In this study, we present the clinical features of both syndromes and their mechanism and discuss the follow-up for this patient and his family.
26 Why Chromosomes Are Relevant Athena M. Cherry, Jesse M. Williams, Jr, Yuen Cho, Rong Luo, Dana Freebury, Charles D. Bangs
237 With the recommendation that chromosomal microarrays be used as a first tier test prenatally, in cases with ultrasound abnormalities, and postnatally, and the looming specter of next generation sequencing (NGS) for copy number changes, the value of routine chromosome analysis is often forgotten. Here we report two examples of important chromosome abnormalities that would have been missed if microarray had been performed without the benefit of karyotypic analysis. The first case is an amniotic fluid study performed on a 29 year old G3P2 woman at 16 weeks 4 days gestation due to a cystic hygroma and a heart defect. Fourteen of 15 in situ colonies had apparently normal 46,XX chromosomes. One whole colony had trisomy 17. This was the seventh colony examined. An additional 12 colonies from three different coverslips were screened for trisomy 17 and one additional trisomy 17 colony was observed. While mosaicism for trisomy 17 is relatively rare, the phenotype can include growth retardation, cardiac anomalies and minor dysmorphic features. The patient was counseled about these risks, but decided to continue. At birth, the cardiac defect was determined to be a ventricular septal defect with a supramitral ring and patent ductus arteriosus. At 2 days of age, a peripheral blood karyotype was performed and showed a normal 46,XX karyotype in all 50 cells examined. This was not unexpected, as cases reported in the literature show confinement of the trisomy 17 cells to fibroblasts. At 17 months of age, the patient showed failure to thrive and developmental delay. During cardiac surgery, skin fibroblasts and subaortic membrane were obtained for chromosome analysis. Four of 20 metaphases examined showed trisomy 17. Had this mother not had prenatal chromosome analysis, this lowlevel (7.4%) mosaicism would have been missed by microarray. As well, performing a limited chromosome analysis of 5 metaphases would have also missed this anomaly. Mosaic trisomy 17 limited to fibroblasts would also never have been suspected in a child with developmental delay and a heart defect. This child would most likely never have a diagnosis. The second case is a blood chromosome analysis performed on a newborn with ambiguous genitalia. Noninvasive prenatal screening (NIPS) had predicted an XX sex chromosome complement. At birth, the infant was small for gestational age and had ambiguous genitalia with fused, rugated labia. A mass was palpated in the right inguinal area. Sex was unassigned with the differential of enlarged clitoris vs. microphallus with penoscrotal hypospadias. STAT chromosomes and SRY FISH were ordered. The first 10 metaphases examined from a 48 hour culture were 45,X. The remaining 10 metaphases showed four cells with what appeared to be an isodicentric of the short arm of the Y chromosome [idic(Y)]. Interphase FISH was positive for SRY in 9 of 100 interphase nuclei examined, while metaphase FISH showed the SRY signal on the idic(Y). Interphase FISH for the X and Y chromosomes showed 146 (73%) with only an X chromosome signal, 28 (14%) with one X and one Y signal, 20 (10%) with one X and three Y signals and 6 (3%) with one X and two Y signals. Individuals with 45,X/46,X,idic(Y) have a wide range of phenotypes from Turner syndrome to normal male with spermatogenic failure. This spectrum can include mixed gonadal dysgenesis and ambiguous genitalia. Interestingly, at 8 months this child was found to have a right undescended testis, a left streak gonad, and a left unicornate uterus, cervix and vagina. The parents have decided to raise him as male. He has had some increase in virilization. Again, it is doubtful that a microarray would have detected this idic(Y). This re-emphasizes that particularly in disorders of sexual differentiation, chromosome analysis is an important first step.