49th Annual Meeting of the American Society of Human Genetics

October 19 - 23, 1999 San Francisco, California


965 The effect of Gravidity and Maternal Age on The First Trimester Down Syndrome Biochemical Markers Free-b hCG and PAPP-A. T.W. Hallahan 1, D.A. Krantz 1, P.D. Buchanan 2, J.W. Larsen, Jr. 3, J. N. Macri 1. 1) NTD Laboratories, Huntington Stat, NY; 2) GeneCare Medical Genetics Center, Chapel Hill, NC; 3) The George Washington Univ. Medical Center, Washington, D.C.

Historically, maternal factors such as weight, ethnicity and diabetic status have been used to adjust second-trimester biochemical markers to refine the screening process and improve false positive and detection rates. The effects of maternal age and gravidity on second-trimester biochemical markers are small and generally do not need to be taken into account. To determine the effect of gravidity and maternal age on first-trimester biochemical markers, dried blood specimens form 1884 patients between 8w2d and 13w6d gestation were analyzed for free-b hCG and PAPP-A. The table shows median weight adjusted MoM levels of free-b hCG and PAPP-A vs. gravida and maternal age.

Gravida

Age

1

2

3

>=4

>=30

30-34

>=35

free-b

0.97

0.99

1.08

1.04

0.95

1.00

1.04

PAPP-A

0.99

0.99

1.02

1.03

0.95

0.99

1.07

 

The rank collection coefficient of free-b with gravidity and age was 0.05 and 0.04 respectively, while for PAPP-A they were .04 and 0.10, respectively. Only the correlation of PAPP-A and age was statistically significant (P<.001), however this association was quite small, especially in light of the association of gravida and age. In conclusion, although maternal age plays a significant role in Down syndrome screening as a major factor in determining prior risk, maternal age and gravidity have little or no effect on the serum levels of first trimester biochemical Down syndrome screening markers.

982 Use of chorionicity to Refine the Risk of Chromosomal Abnormalities in Twin Pregnancy. D.A. Krantz 1, T.W. Hallahan 1, J.W. Larsen, Jr. 2, P.D. Buchanan 3, R.J.M. Snijders 4, V. Klein 5, J.N. Macri 1. 1) NTD Laboratories, Huntington Stat, NY; 2) The George Washington Univ., Washington, D.C.; 3) GeneCare Medical Genetics Center, Chapel Hill, NC; 4) Cedar Sinai Medical Center, Los Angeles, CA; 5) North Shore Univ. Hospital, Manhasset, NY.

Information regarding the risk of chromosomal abnormality in one or both fetuses in a twin pregnancy assists patients in making decisions regarding invasive diagnostic procedures. Risks can be determined based on the percentage of twins that are dizygotic (Rodi et al 1990). However, zygosity can not easily be determined at this stage of pregnancy. Chorionicity is not synonymous with but can be used to give an indication of zygosity. A 10-14 week scan can determine dichorionicity (lambda-sign or twin peak) or monochorionicity (T-sign) by paying specific attention to the junction of the intertwin membraine and placenta. It is estimated that about 2/3 of twins are dizgotic and 1/3 are monozygotic. All dizygotic twins are dichorionic. Of monozygotic twins, about 2/3 are monochorionic and 1/3 are dichorionic. These figures may vary depending on other factors such as ethnicity or if twinning is spontaneous or induced. Bayes’ rule can be used to determine the likelihood of zygosity based on chorioncity. Using the above percentages, all monochorionic pregnancies are monozygotic while 86% of dichorionic pregnancies are dizygotic. The table below gives an example of how chorionicity determined from U/S can refine the risk of Down syndrome for a 32 year old patient:

Singleton

Twins

Monochorionic

Dichorionic

At least 1 Affected

1/659

1/395

1/659

1/355

Both Affected

-----

1/1991

1/659

1/4571

This approach could be developed for Down Syndrome screening based on biochemistry and NT as well as maternal age.

 

 

2071 Nuchally Translucency Measurement in Twin Pregnancy. J.N. Macri 1, D.A. Krantz 1, T.W. Hallahan1, P. D. Buchanan 3, F. Orlandi 4, C. Rossi 4, L. Dugoff 5. 1) NTD Laboratories, Huntington Station, NY; 2) The George Washington Univ. Medical Center, Washington, D.C.; 3) GeneCare Medical Genetics Center, Chapel Hill, NC; 4) Centro Di Diagnosi Prenatale, Palermo, Italy; 5) Univ. of Colorado, Denver, CO.

Maternal factors have been used to adjust biochemical marker levels when screening for Down syndrome and open neural tube defects. To date, no maternal factors have been identified which effect nuchal transluceny (NT) measurements. If the NT measurement of each fetus in a twin pregnancy tended to be similar, this might indicate that there are as yet unidentified maternal factors that effect NT values. A total of 32 first-trimester clinically normal twin pregnancies between gestional ages 10w4d and 13w6d in which NT was measured in both fetuses wer analyzed. Using an analysis of variance procedure, data were analyzed to determine whether there was greater variation i NT measurements from woman-to-woman than between the twin fetuses in each pregnancy. Since NT increases with crown rum length data were analyzed using NT MoM results. The variance within the twin pairs was 42% of the variance among the twin pregnancies (.0651 vs. .1533). This was a significant difference (p=.009). To rule out operator variation as a cause of these results, a subset of 13 cases were analyzed in which the same operator performed all of the measurements. In this subset, the variance within the pairs was still less than the variance among the twin pregnancies (.0652 vs. .1065), however, this difference was not statistically significant. In conclusion, the data indicate that the 2 NT values in twin pregnancies tend to be associated although the association is not as strong when the measurement is performed by single operator. This information suggests the possibility that maternal factors may affect the degree of nuchal translucency in the fetus.

 

20 Autosomal XX sex reversal caused by duplication of SOX9. B. Huang 1,2, S. Wang 3, Y. Ning 4, A.N. Lamb 5, J. Bartley 1. 1) Genzyme Genetics, Orange, CA; 2) University of California Irvine; 3) Harbor-UCLA Medical Center, Torrance, CA; 4) GeneCare Medical Genetics Center and the George Washington University, Washington, DC; 5) Genzyme Genetics, Santa Fe, NM.

SOX9 is one of the genes that play critical roles in male sexual differentiation. Mutations of SOX 9 leading to haploinsufficiency can cause campomelic dysplasia and XY sex reversal. We present here the evidence supporting that SOX9 duplication can cause XX sex reversal.

A new born was referred to genetic evaluation due to ambiguous genitalia. The newborn had incomplete masculinization with severe penile/scrotal hypospadias. The gonads were palpable. Congenital adrenal hyperplasia was not identified as the serum analysis revealed a mosaic 46,XX,dup(17) (q23.1q24.3)/46,XX karyotype. The dup (17) was observed in 34% of lymphocytes and 78% of the skin fibroblasts. Fluorescence in situ hybridization (FISH) with a BAC clone containing SOX9 gene demostrated that the SOX9 gene is duplicated on the rearranged chromsome 17. The presence of SRY was ruled out by FISH with a SRY probe and PCR with SRY-specific sprimers. Microsatellite analysis with 13 markers on 17q23-24 suggests that the mechanism of the duplication is consistent with maternal mitotic unequal cross-over and defined the boundary of duplication to be approximately 12 centromorgans (cM) proximal and 4 cM distal to the SOX9.

Since SOX9 plays a critical role in male sexual determination and differentiation, its duplication apparently is the most likely etiology for causing the sex reversal in this case. To our knowledge, this is the first autosomal gene reported to be associated with XX sex reversal. Our study suggests that extra dosage of SOX9 is sufficient to initiate testis differentiation in absence of SRY. In addition, this study warrants thorough investigation of SOX9 function in other SRY negative XX sex reversal individuals, including study cell types other than lymphocytes.
Abstracts Continued
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