Biomedical subjects
Publications and source records attributed to M C Phelan.
Mosaicism for the Wolf-Hirschhorn syndrome, del(4)(p16), is extremely rare and has not been reported in association with a numerical chromosome abnormality. We report the prenatal diagnosis of mosaic del(4)(p16) and non-mosaic trisomy 21 in a 16-week female fetus. The pregnancy ended in spontaneous abortion at 34 weeks secondary to fetal demise. The fetus had features of both 4p- and trisomy 21.
A deletion of 7q21.2-q22.1 has been found in a patient with split foot and developmental retardation. Molecular analysis using polymerase chain reaction (PCR) showed deletion of three microsatellite markers, D7S527, D7S479 and D7S554, in the patient's paternal chromosome. These results pinpoint the critical region for an ectrodactyly locus (SHFD1) on chromosome 7.
The full FMR-1 mutation is known to cause the fragile X syndrome [Fra(X)], but variable expression in females, including normal to deficient intellect, may be related to random X-inactivation (lyonization). We have evaluated 2 mosaic 45,X/46,XX females who are cytogenetically fra(X) positive, have an FMR-1 full mutation, and are of normal intellect. There were 50% fra(X) chromosomes in the 45,X cells of one of the females; this has not been reported previously. In both patients, there was a strong asymmetry of FMR-1 methylation with the normal allele being totally or 90% unmethylated and the mutant allele being similarly methylated. Thus, the apparent selective inactivation of the full mutant FMR-1 allele appears to have resulted in limited expression with normal intellect. The presence of the fra(X) chromosome in 45,X cells is unique; however, there may be no relationship to the asymmetric inactivation of the mutant allele which could be due to chance or a mechanism yet to be delineated.
We describe 4 patients with facial changes of Brachmann-de Lange syndrome but without limb defects. Mental retardation ranged from moderate to severe and the degree of prenatal and postnatal growth deficiency was variable. These patients exemplify the diagnostic difficulties and counseling dilemmas posed by the mild Branchmann-de Lange phenotype. The relationship of the mild phenotype to the full syndrome will not be understood until the pathogenetic or causal factor(s) are delineated.
We evaluated 10 patients with an inverted tandem duplication of 8p. Inverted duplications of chromosome 8 have been reported infrequently, and no syndrome has been previously identified. All 8 patients on whom birth histories were available were hypotonic at birth, and had feeding difficulties in the neonatal period. All patients have significant developmental delay. Manifestations present in 5 or more patients were prominent forehead, high arched palate, large mouth with a thin upper lip, malformed and/or apparently low-set ears, broad nasal bridge, dental and skeletal abnormalities, and joint laxity or hyperextensibility. Variation in the phenotype may, in part, be explained by the different breakpoints. Recurrence risks of de novo rearrangements are probably very low, but for the recombinants the risk may be significant. The duplication appeared to be de novo in 6 patients (both parental karyotypes were normal); maternal karyotypes were normal in 2 patients, and both parents of 1 patient were not available. One propositus had a monocentric recombinant of a paracentric inv(8) (p12p23.3) carried by the mother, and is one of only 6 known cases of duplication associated with a balanced paracentric inversion in a parent. The carrier parent was the mother in 5 of those 6 cases. Each case involved a different chromosome, and each probably was created by an unusual meiotic recombination event. Inverted duplication 8p is one of the most common duplications observed in our laboratories, and ranks in frequency with the classical deletions, such as Wolf-Hirschhorn and cri-du-chat syndromes and duplication or secondary trisomy 15q1.(ABSTRACT TRUNCATED AT 250 WORDS)
Chromosomally unbalanced offspring resulting from the recombination of parental paracentric inversions are uncommon. We report on a 20-month-old boy with a partial duplication of 9p due to the recombination of a paternal paracentric inversion. The patient's recombinant chromosome was designated rec(9)(p13-->p24::p12-->p24::p12-->qter). The patient's father and paternal aunt have a paracentric inversion of chromosome 9:inv(9)(p13p24). Although several mechanisms have been proposed to explain the chromosome imbalance generated from paracentric inversions, none of the previously described mechanisms can account for the structure of the recombinant chromosome observed in the propositus. We propose an unusual mechanism of formation involving breakage and unequal reunion of sister chromatids within the inversion loop to explain the structure of the patient's recombinant chromosome.
DNA at the FMR-1 locus was analyzed by Southern blot using probe StB12.3 in an unusual fragile X family with six brothers, three of whom are affected with fragile X to varying degrees, two of whom are nonpenetrant carriers, and one of whom is unaffected. Fragile X chromosome studies, detailed physical examinations, and psychological testing were completed on all six. Two of the affected brothers and the two nonpenetrant brothers were found to be methylation mosaics. The three affected males spanned the phenotypic and cognitive spectrum of the fragile X syndrome. A correlation was seen between the degree of methylation and the phenotypic expression identified in the three affected males. The two males initially classified as nonpenetrant were found to have mild phenotypic expression which consisted of minor cognitive deficits and a partial physical phenotype. These two, who were negative on fragile X chromosome studies, were found on DNA analysis to have large broad smears, with approximately 97% of the DNA unmethylated. The results described here indicate that some "nonpenetrant" carrier males may have varying amounts of methylation of the FMR-1 region, which can result in mild expression of the fragile X syndrome. The apparently mild phenotypic and cognitive expression of the fragile X syndrome in the two males, initially classified as nonpenetrant, who are mosaic for hypermethylation of an expansion of the CGG repeat in the premutation range, indicates that expression of the syndrome is not confined to males with large, hypermethylated expansions (full mutation) but has instead a gradient effect with a threshold for the full expression of the phenotype.
We report on a 3-year-old boy with a terminal deletion of 22q. The activity of alpha-N-acetylgalactosaminidase was normal while arylsulfatase A activity was reduced. Molecular analysis demonstrated the lack of paternal alleles of D22S45 and D22S55.
DNA from a male fetus with an interstitial deletion of 7q22 [(46,XY,del(7)(pter----q22.10::q31.10----qter)] was analyzed using probes in this region of 7q. The results localize plasminogen activator inhibitor type I (PLANH1) to 7q22.1----q22.3 and beta-glucuronidase to band 7q21.11.
We observed a paracentric inversion of 19p in a 15-month-old white boy with developmental delay and mild facial anomalies. The inversion of 19p was also present in his phenotypically normal mother and maternal grandfather.
A woman with an abnormal karyotype, (46,X,der(X) (pter----q27::q27----q21), was analyzed using DNA probes in the region Xq27----qter. The results indicate that she is trisomic for the Factor IX locus, disomic for the locus DXS105 (cX55.7) and monosomic for the loci DXS98 (4D8), DXS52 (St14) and Factor VIII. This confirms the absence of the region Xq28 in the abnormal chromosome. Furthermore, the presence of only one copy of 4D8 and two copies of cX55.7 places the DXS98 locus distal to Factor IX and closer to the fragile X locus than DXS105.
Cytogenetic and molecular analyses of three dicentric X chromosomes were performed in an attempt to identify the parental origin and mechanism of formation of the aberrant chromosomes. Results indicate that, in these three cases, the dicentric chromosomes were formed by chromatid breakage and reunion of sister chromatids at the breakpoint. In two cases the abnormal chromosomes were paternal in origin; in the third case the dicentric originated from the maternal X chromosome.
Genomic single-copy DNA fragments were used to characterize an undetected chromosome translocation in an individual whose metaphase chromosome analysis revealed apparent monosomy 21. Eight RFLPs detected by six probes were used to identify homologous sequences from chromosome 21 in DNA digests from the proband and her parents. These family studies showed that the proband was disomic for the distal region of 21q. Reverse banding and in situ hybridization of chromosome 21-specific probes to metaphase chromosomes from the proband revealed a de novo translocation with breakpoints at 5p13 or 14 and 21q11 or 21. In situ hybridization permitted orientation of the translocated portion of chromosome 21 on the derivative chromosome 5 and, in conjunction with molecular analysis and previous mapping studies, refined the physical map for the long arm of chromosome 21.
The Miller-Dieker syndrome (MDS), a syndrome with lissencephaly, distinctive craniofacial features, growth impairment, and profound developmental failure, has been associated with a deletion of the distal part of chromosome band 17p13. A minority of patients with the syndrome do not have a deletion detectable with current cytogenetic techniques. Using three highly polymorphic DNA probes (pYNZ22, pYNH37.3, and p144D6) we have detected microdeletions in three MDS patients, two of whom had no visible abnormalities of chromosome 17. Loci defined by two of the DNA probes, pYNZ22 and pYNH37.3, were deleted in all three patients. The most distal locus, defined by p144D6, was present in one MDS patient, possibly defining the distal limits of the MDS region in band 17p13.3. None of these loci were absent in one case of lissencephaly without MDS.
Two sisters with premature menopause and a small deletion of the long arm of one of their X chromosomes [del (X)(pter----q26.3:)] were investigated with polymorphic DNA probes near the breakpoint. The deleted chromosome retained the factor IX (F9) locus and the loci DXS51 (52A) and DXS100 (pX45h), which are proximal to F9. However, the factor VIII (F8) locus was not present, nor were two loci tightly linked to this locus, DXS52 (St14) and DXS15 (DX13). This deletion refines the location of the F9 locus to Xq26 or to the interface Xq26/Xq27, thus placing it more proximally than has been previously reported. The DNA obtained from these patients should be valuable in the mapping of future probes derived from this region of the X chromosome.
A hypothesis is set forth that neural tube defects are produced by inadequate nutrient supply to the rapidly growing neural folds. According to this hypothesis, a delay in establishing blood flow or an aberration of blood supply to neural tissue may interfere with nutrition and prevent neural tube closure. The hypothesis was tested by examining the vasculature of fetuses with spinal neural tube defects. In each case, the arterial supply to the region of the neural tube defect was disturbed. Because development of arterial supply to the neural folds predates neural tube closure, these vascular abnormalities are considered to be primary malformations that lead to neural tube defects rather than secondary morphologic disturbances resulting from neural tube defects.
Dissection of the abdominal vasculature in 11 cases of sirenomelia has demonstrated a pattern of vascular abnormalities that explains the defects usually found in this condition. The common feature is the presence of a single large artery, arising from high in the abdominal cavity, which assumes the function of the umbilical arteries and diverts nutrients from the caudal end of the embryo distal to the level of its origin. The steal vessel derives from the vitelline artery complex, an early embryonic vascular network that supplies the yolk sac. Arteries below the level of this steal vessel are underdeveloped and tissues dependent upon them for nutrient supply fail to develop, are malformed, or arrest in some incomplete stage. In contrast to the prevailing view that sirenomelia arises by posterior fusion of the two developing lower limbs, these studies suggest that the single lower extremity in sirenomelia arises from failure of the lower limb bud field to be cleaved into two lateral masses by an intervening allantois.