Jacquelyn Roberson

Mental retardation in Turner syndrome

intestinal chloride transport in cystic fibrosis. FASEB J 1988;2:2625-9. 7. Orlando RC, Powell DW, Croom TD, et al. Colonic and esophageal transepithelial potential difference in cystic fibrosis. Gastroenterology 1989;96:1041-8. 8. Powell DW. Ion and water transport in the intestine. In: Anreoli TE, Hoffman DE, Fanestil DD, et al, eds. Physiology of membrane disorders. New York: Plenum Press, 1986;559-96. 9. Goldstein JL, Nash NT, AI-Bazzaz F, et al. Rectum has abnormal ion transport but normal cAMP-binding proteins in cystic fibrosis. Am J Physiol 1988;254:C719-24. 10. Rask-Madsen J, Schiotz PO, Bartels U, et al. Electrical polarization of rectal mucosa and excretion of tetrahydroaldosterone in patients with cystic fibrosis of pancreas and in normal subjects. Acta Paediatr Scand 1975;64:81-6. 11. Rechkemmer G, Halm D, Work J, et al. Independent regulation of potassium transport and sodium absorption by aldosterone in guinea pig distal colon [Abstract]. Fed Proc 1987;46:635A.

Prenatal diagnosis of 22q11.2 deletion when ultrasound examination reveals a heart defect

Purpose: The incidence of 22q11.2 deletion syndrome is approximately 1 in 5,000 births, and accounts for 5–30% of all heart defects, making it one of the more common genetic conditions in the population.Methods: We employed fluorescence in situ hybridization (FISH) to study the incidence of 22q11.2 deletions in fetuses with cardiac anomalies detected on ultrasound examination.Results: Of 64 cases, 18 had visible chromosome anomalies. FISH testing for 22q11.2 deletion was performed on the remaining 46 cases, and five exhibited a 22q11.2 deletion. Three of the five had de novo deletions, one was maternally inherited, and one family declined testing.Conclusion: FISH analysis for 22q11.2 deletion should be performed on all fetuses with cardiac defects (excluding hypoplastic left heart and echogenic focus) and a normal G-banded karyotype.

Frequency of genomic rearrangements involving the SHFM3 locus at chromosome 10q24 in syndromic and non-syndromic split-hand/foot malformation

Split‐hand/foot malformation (SHFM), or ectrodactyly, is characterized by underdeveloped or absent central digital rays, clefts of the hands and feet, and variable syndactyly of the remaining digits. SHFM occurs as both an isolated finding and a component of many syndromes. SHFM is a heterogeneous condition caused by multiple loci, including SHFM1 (chromosome region 7q21‐q22), SHFM2 (Xq26), SHFM3 (10q24), SHFM4 (3q27), and SHFM5 (2q31). Mutations in TP63 at the SHFM4 locus are known to underlie both syndromic and non‐syndromic forms SHFM, but the causes of most non‐syndromic SHFM cases remain unknown. The recent identification of submicroscopic tandem chromosome duplications affecting the SHFM3 locus in seven families with non‐syndromic SHFM has helped to further unravel the molecular basis of this malformation. In our ongoing studies of the SHFM3 locus in 44 additional cases of syndromic and non‐syndromic SHFM, we have identified similar chromosome rearrangements in eight additional cases (18%), using pulsed‐field gel electrophoresis (PFGE). We have also utilized real‐time quantitative PCR (qPCR) to test for the duplications. Seven of the cases with rearrangements were non‐syndromic. The current findings bring the total of SHFM3‐associated cases with chromosome rearrangements to 15, which constitute 29% (15 of 51) of the cases screened to date. This includes 9 of 9 cases (100%) with known linkage to the SHFM3 locus, all of whom have non‐syndromic SHFM, and 6 of 42 additional cases (14%), four of whom have non‐syndromic SHFM. Thus, SHFM3 abnormalities underlie a substantial proportion of SHFM cases and appear to be a more frequent cause of non‐syndromic SHFM than mutations in TP63.

Duplication 6q21q23 in two unrelated patients

We report on two patients with rare 6q duplications. The karyotype of patient 1 is 46,XY,dup(6)(q21q23.3). The karyotype of patient 2 is 46,XX,dup(6)(q21.15q23.3). These two patients have some nonspecific physical findings in common including a depressed nasal bridge, epicanthal folds, mild heart defects, and developmental delay, but each had other congenital anomalies.

A Novel SERPINA1 Mutation Causing Serum Alpha1-Antitrypsin Deficiency

Mutations in the SERPINA1 gene can cause deficiency in the circulating serine protease inhibitor α1-Antitrypsin (α1AT). α1AT deficiency is the major contributor to pulmonary emphysema and liver disease in persons of European ancestry, with a prevalence of 1 in 2500 in the USA. We present the discovery and characterization of a novel SERPINA1 mutant from an asymptomatic Middle Eastern male with circulating α1AT deficiency. This 49 base pair deletion mutation (T379Δ), originally mistyped by IEF, causes a frame-shift replacement of the last sixteen α1AT residues and adds an extra twenty-four residues. Functional analysis showed that the mutant protein is not secreted and prone to intracellular aggregation.

868 A PRACTICAL METAPHASE MARKER OF THE INACTIVE X CHROMOSOME

The ability to identify the inactivated X chromosome with routine G- or Q-banding would have broad clinical and research applicability. We recently reported that the inactivated X frequently bends or folds in region Xql3Xq21 (Flejter et al, Am J Hum Genet 36:218, 1984). The fold occurs in about 88% of prometaphase, 50% of early metaphase, 30% of midmetaphase, and 10% of late metaphase inactive Xs. In prometaphase, the site of folding includes Xq11.2 and Xq13.3, infrequently extending to Xq21.1. An omega-shaped loop is frequently formed between sub-bands Xq11.2 and Xq13.3. It is paradoxical that the inactive X is the only chromosome identifiable in interphase, yet in metaphase it cannot be distinguished from its active homolog. The specific inactivation-associated fold at region Xq1 resolves that paradox and is a useful marker of the inactive X. 1. The KOP translocation, t(X; 14)(q13; q32), has nearly all of Xq translocated to 14q (Allerdice et al, Am J Med Genet 2:223, 1978). Cell line GM0074 has one normal 14, one Xq-, two der (14) chromosomes, and a Y. One der(14) folded in 10/18 cells scored, confirming translocation of the inactivation center adjacent to 14q distal. 2. Metaphase cells from other primates had a specific fold in the same region as in the human X: at Xq13-Xq21 in 2 gorillas, 1 chimp, 2 pygmy chimps, 1 orang, 1 baboon, 1 rhesus and 1 stump-tail monkey. This is further evidence for evolutionary conservation of the X chromosome. One chimpanzee exhibited the fold at Xq24; we suspect a pericentric inv in this individual. We have not seen a frequent fold in the X of a bat (Tadarida brasiliensis), Chinese hamster (Cricetulus griseus), or rat kangaroo (Potorous tridactylis). 3. Regarding the relationship of X inactivation and intelligence in fra(X)(q28) carriers, we observe that in cells of normal carriers the fold was mostly on the fragile X-positive chromosome, whereas in cells of an affected carrier the fold was mostly on the fragile X-negative chromosome. This is evidence that inactivation of the fragile X chromosome is positively correlated with intelligence in carriers.

PRENATAL DIAGNOSIS OF A GIRL WITH MUSCULAR DYSTROPHY CAUSED BY DE NOVO t|[lpar]|X;4|[rpar]| |[lpar]|p21;q35|[rpar]|

In May, 1983 we obtained amniotic fluid for chromosome studies from a couple who were both 31 years old. The indication was parental anxiety because the mother worked closely with mentally retarded adults. The amniotic fluid cell karyotype was female with a balanced translocation: 46,X,t(X;4)(p21;q35) with the normal X preferentially inactivated. Alpha fetoprotein and detailed ultrasound examinations were normal. Chromosome studies of the parents were normal, so the translocation apparently arose as a new mutation.Two special circumstances complicated the counseling. First, a de novo rearrangement ascertained by amniocentesis carries roughly a 5% increased risk of birth defects over the general 3-5% population incidence of birth defects, but the available risk estimates do not appear to include the risk of mental retardation without malformation, since follow-up has been sporadic of such cases identified prospectively. Second, in a balanced X/autosome translocation the structurally normal X is genetically inactivated, which allows expression of any abnormal genes on the translocation X. There are at least 13 other girls with Duchenne muscular dystrophy who carry a de novo X/autosome translocation with a breakpoint at Xp21. In the absence of a family history of muscular dystrophy, these findings suggest a point mutation due to the break at Xp21.We advised the parents that the fetus was at some increased risk (of uncertain magnitude) for having malformations, retardation, or muscular dystrophy. The couple continued the pregnancy. At age 3 months, the infant has a normal appearance, developmental milestones and neurologic exam. However, at 24 hours of age her serum CPK was 21,450 IU/L. Subsequent values were 1,260 and 3,100 at 1 and 3 months, respectively. Such neonatal and infancy levels of CPK are strongly suggestive of Duchennes muscular dystrophy.