D. L. Van Dyke

Redefining the risks of prenatally ascertained supernumerary marker chromosomes: a collaborative study

Background: A marker chromosome is defined as a structurally abnormal chromosome that cannot be identified by routine cytogenetics. The risk for phenotypic abnormalities associated with a marker chromosome depends on several factors, including inheritance, mode of ascertainment, chromosomal origin, and the morphology, content, and structure of the marker. Methods: to understand the karyotype-phenotype relationship of prenatally ascertained supernumerary de novo marker chromosomes, we combined data from prenatal cases obtained from 12 laboratories with those from studies in the literature. We were able to obtain cytogenetic and phenotypic data from 108 prenatally ascertained supernumerary de novo marker chromosomes to refine the phenotypic risk associated with these markers. Because of the growing number of cases and because more techniques are available to delineate marker morphology, we have been able to group risk estimates into subcategories, such as by marker type and whether there are ultrasound abnormalities. Results: If a de novo supernumerary marker chromosome is found prenatally, our data suggest there is a 26% risk for phenotypic abnormality when there is no other information defining the marker (such as chromosomal origin or information about the existing phenotype). However, if high resolution ultrasound studies are normal, this risk reduces to 18%. Conclusions: Our findings strongly support the value of additional genetic studies for more precisely defining the risk in individual cases involving marker chromosomes.

Prenatal identification of a girl with a t(X;4)(p21;q35) translocation: molecular characterisation, paternal origin, and association with muscular dystrophy.

There are 23 females known with Duchenne or Becker muscular dystrophy (DMD or BMD) who have X;autosome translocations that disrupt the X chromosome within band p21. A female with a t(X;4)(p21;q35) translocation was identified prenatally at routine amniocentesis. At birth, she was found to have a raised CK level, consistent with a diagnosis of Duchenne muscular dystrophy. Her cells were fused with mouse RAG cells and the translocated chromosomes were separated from one another and from the normal X chromosome by segregation in the resulting somatic cell hybrids. Southern blot analysis of the hybrids indicated that the translocation occurred on the X chromosome between genomic probes GMGX11 and J-66, both of which lie within the DMD gene. Further localisation with a subfragment of the DMD cDNA clone placed the translocation breakpoint in an intron towards the middle of the gene, confirming that the de novo translocation disrupted the DMD gene. RFLP analysis of the patient, her parents, and the hybrid cell lines showed that the translocation originated in the paternal genome. This brings to six out of six the number of DMD gene translocations of paternal origin, a fact that may be an important clue in future studies of the mechanism by which X;autosome translocations arise.

Deletion of 2q37 and duplication of 10q24: Two cases in the same family and review of the literature

We describe two patients (first cousins, once removed) with an unusual head shape, high arched palate, flat nasal bridge, abnormal ears, hand and feet abnormalities and other anomalies. The patients were ascertained independently and it was initially unknown that they were related to each other. Cytogenetic and fluorescent in situ hybridization (FISH) analysis identified a der(2)t(2;10)(q37.3;q24.1) unbalanced translocation resulting in loss of 2q37.3-qter and duplication 10q24.1-qter. The clinical features of these two patients are compared with previously described cases of 2q deletion and 10q duplication. These patients also emphasize the difficulty in some families of understanding and sharing genetic information and in the difficulties in obtaining an accurate pedigree in a genetics clinic.

A patient with Gorlin‐Chaudhry-Moss syndrome and del(9)(q22.1q22.3)

We report a patient with a rare 9q deletion and features of Gorlin-Chaudhry-Moss syndrome (GCM). At age 3, the patient presented with acrocephaly, small maxilla, low frontal hairline, two occipital hair whorls, epicanthal folds, hypotelorism and prominent eyes with strabismus and nystagmus, and oval irides. She also had synophrys, low set ears, a tuft of hair on her nose, cleft tip of the nose, thin upper lip, downtumed corners of the mouth, high arched palate, webbing between the gums and buccal mucosa, wide alveolar ridge and dental anomalies including fusion of some teeth, mild pectus excavatum, 5th finger clinodactyly, left transverse palmar crease, short 4th metacarpals, overlapping toes 2-3, and thoracic scoliosis. She had persistent rhinorrhea and serous otitis media requiring PE tubes. She was not walking or talking. Karyotype was 46, XX, del(9)(q22.1q22.3). Mothers karyotype was normal and father was unavailable. CT scan identified agenesis of the corpus callosum. At age 21 she had moderate mental retardation and spoke in short phrases with unclear speech. Numerous scars on her arms were secondary to skin picking. Surgeries included spinal fusion with Harrington rod placement and removal of 5 odontogenic cysts. Right retinal detachment and cataract had occurred and she continued to have rhinorrhea and serous otitis. Acrocephaly, coarse facies, shallow orbits with prominent eyes, oval irides, synophrys, right ptosis, midface hypoplasia, prominent chin, hypodontia, short 4th metacarpals, and hypoplastic and dysplastic finger and toenails were noted.GCM was first reported in sisters with craniofacial dysostosis, hypertrichosis, dental and eye anomalies, patent ductus arteriosus, and mental retardation. Other features included short 4th metacarpals and distal phalanges. Two other unrelated females have been identified and all four patients had hypertrichosis, low frontal hairline, conductive hearing loss, and coarsening of facial features with time. Autosomal recessive inheritance was postulated.We are unaware of other subjects with this deletion though 9q22-q32 deletions have been reported to have mental retardation, seizures, hypotelorism, sclerocornea, duodenal atresia, malrotation, hydronephrosis, preaxial polydactyly and syndactyly of the toes. Our findings suggest that GCM may represent a contiguous gene syndrome residing within the 9q22.1-q22.3 segment. Our patients more severe mental retardation may be secondary to deletion of other genes on 9q.