WEBVTT 00:00.000 --> 00:30.000 position:50% align:top line:0% *This machine-generated transcript may have errors. If remediation or a manually-generated transcript is needed, please contact NLM Support at https://support.nlm.nih.gov.* 00:04.040 --> 00:04.460 Mhm. 00:15.740 --> 00:15.950 A. 00:15.950 --> 00:18.830 United States Army Medical Department continuing 00:18.830 --> 00:20.260 education program, 00:22.310 --> 00:25.020 The 24th annual Armed Forces seminar on 00:25.020 --> 00:26.950 obstetrics and gynecology, 00:29.540 --> 00:31.810 genetics of spontaneous abortion 00:35.040 --> 00:37.700 and heritable aspects of common 00:37.700 --> 00:39.450 gynecological disorders 00:42.340 --> 00:43.570 with Jolie Simpson, 00:43.570 --> 00:44.260 MD. 00:44.740 --> 00:46.150 Associate professor O. 00:46.150 --> 00:46.330 B. 00:46.330 --> 00:46.540 G. 00:46.540 --> 00:46.730 Y. 00:46.730 --> 00:46.910 N. 00:46.910 --> 00:47.550 Department, 00:47.930 --> 00:50.200 Northwestern University Medical School, 00:50.210 --> 00:51.550 Chicago Illinois. 00:53.940 --> 00:54.870 In a nutshell, 00:54.870 --> 00:55.570 as we all know, 00:55.570 --> 00:58.500 the extent of spontaneous abortion is really 00:58.500 --> 00:59.600 quite large. 00:59.610 --> 01:02.550 Uh We could draw some fancy graphs and 01:02.550 --> 01:05.200 show you that only a small portion of all 01:05.200 --> 01:08.000 concept asses ever make it to the to the live born 01:08.000 --> 01:08.510 nursery. 01:08.520 --> 01:10.860 Uh And let's just consider this. 01:11.240 --> 01:14.140 We can divide this really into about three major 01:14.140 --> 01:14.550 groups. 01:14.550 --> 01:15.700 First of all, 01:15.710 --> 01:18.060 the pregnancies are 01:18.070 --> 01:19.930 embryos that have reached. 01:19.930 --> 01:22.690 So shall we say the pre clinical stages, 01:22.700 --> 01:25.080 that is embryos that are less than 01:25.080 --> 01:28.040 about four weeks of embryonic age, 01:28.050 --> 01:30.860 less than six weeks or even four weeks from the 01:30.860 --> 01:32.010 last menstrual periods. 01:32.010 --> 01:32.560 In other words, 01:32.560 --> 01:34.660 conditions uh 01:35.040 --> 01:37.950 Pregnancies in which we have not recognized in by our 01:37.950 --> 01:39.530 conventional techniques, 01:39.540 --> 01:42.140 secondly clinically recognisable 01:42.150 --> 01:43.040 pregnancies. 01:43.040 --> 01:45.980 Those uh first trimesters if you will, 01:45.980 --> 01:48.110 in which spontaneous abortion occurs. 01:48.120 --> 01:50.680 And finally uh those 01:50.750 --> 01:52.760 2nd and 3rd trimester 01:53.140 --> 01:55.560 abortions or stillbirths if you will. 01:56.040 --> 01:58.650 So here are three major groups that we can focus on. 01:59.540 --> 02:02.200 There's really been only one attempt uh to my 02:02.200 --> 02:05.180 knowledge to assess the incidence 02:05.190 --> 02:08.050 of embryonic abnormalities that occur 02:08.050 --> 02:10.760 prior to the time of clinically recognized pregnancy. 02:10.760 --> 02:12.650 And this was done in the in the 50s. 02:12.650 --> 02:15.600 But I heard he can rock and they did a very interesting 02:15.600 --> 02:17.750 series of I guess we could call it 02:17.750 --> 02:18.880 experiments. 02:18.890 --> 02:21.570 I'm not sure we would get this past the human 02:21.570 --> 02:24.510 ethics committee these days but such 02:24.510 --> 02:25.310 as progress. 02:25.350 --> 02:26.300 At any rate, 02:26.310 --> 02:28.900 they took a series of women at the boston lying in 02:28.900 --> 02:31.460 hospital who were uh going to 02:31.460 --> 02:34.300 undergo a hysterectomy for one reason or the other, 02:34.300 --> 02:35.660 usually from my Omagh's. 02:36.040 --> 02:38.960 And they requested that they take their basal body 02:38.960 --> 02:41.340 temperature and then at various 02:41.350 --> 02:43.710 periods of time thereafter, 02:43.720 --> 02:45.980 depending upon when they had undergone, 02:45.980 --> 02:47.980 were scheduled to undergo their operation. 02:47.990 --> 02:50.670 Um They entered the hospital so that 02:50.680 --> 02:53.680 uh these investigators in new the time 02:53.680 --> 02:56.450 in which the biphasic curve rose and 02:56.450 --> 02:59.380 presumably which ovulation took place. 02:59.390 --> 03:01.150 And then they then took the 03:01.740 --> 03:04.720 specimens that clamp both fallopian 03:04.720 --> 03:07.400 tubes as well as blocked the cervix and 03:07.400 --> 03:09.740 first flushed out sequentially the 03:09.740 --> 03:12.660 tubes and the uh endometrial area 03:12.660 --> 03:15.550 to try to find any free line blastocyst. 03:15.550 --> 03:15.660 Now, 03:15.660 --> 03:16.170 you recall, 03:16.170 --> 03:18.590 it takes about three days from the time of 03:18.600 --> 03:19.470 population. 03:19.480 --> 03:21.150 Uh The album, 03:21.540 --> 03:24.140 using the term loosely as it's used in medicine, 03:24.150 --> 03:26.740 is in the fallopian tubes for about three 03:26.740 --> 03:29.330 days and then it's free lining the endometrium 03:29.330 --> 03:32.090 cavity for another three days prior to its time of 03:32.090 --> 03:32.980 implantation. 03:32.990 --> 03:33.610 So, 03:33.610 --> 03:34.530 by flushing out, 03:34.530 --> 03:35.430 First of all, 03:35.500 --> 03:38.110 they could obtain any embryos that were 03:38.110 --> 03:40.350 less than about six days of, 03:40.360 --> 03:41.340 of age. 03:41.350 --> 03:42.240 And in doing so, 03:42.240 --> 03:44.980 they noted that four of the eight that they 03:44.980 --> 03:47.890 detected were so abnormal in terms of 03:47.890 --> 03:50.730 morphology than it was practically 03:50.730 --> 03:52.570 inconceivable in their words, 03:52.580 --> 03:54.970 that continued pregnancy could have occurred. 03:54.980 --> 03:55.690 And therefore, 03:55.690 --> 03:58.580 since we're talking about the period of time prior 03:58.580 --> 04:01.010 to the expected men sees, 04:01.130 --> 04:04.050 it was most likely that this individual never would have known that 04:04.050 --> 04:04.750 she was pregnant. 04:04.760 --> 04:07.220 To begin with the 04:07.230 --> 04:09.700 second piece of the uh their 04:09.700 --> 04:12.160 investigation was that they then look at the 04:12.170 --> 04:14.890 implant it Blastocyst. 04:15.220 --> 04:18.090 Now the ages arranging from somewhere around 04:18.090 --> 04:20.300 seven to about 21 days 04:20.530 --> 04:23.370 past the date of ovulation or in other words, 04:24.040 --> 04:26.890 had two more to that if you want to get the minstrel age as we 04:26.890 --> 04:29.870 usually tail in clinical 04:29.870 --> 04:30.620 obstetrics. 04:30.920 --> 04:32.090 And in doing so, 04:32.100 --> 04:35.050 I think you can show the first slide the next set. 04:35.540 --> 04:36.880 And in doing so, 04:36.910 --> 04:39.850 they noted that eight of the 26 04:39.860 --> 04:42.680 implanted blastocyst less than about 04:42.690 --> 04:45.610 2 to 3 weeks of embryonic age were grossly 04:45.610 --> 04:46.290 abnormal, 04:46.300 --> 04:48.670 so that the incidence of fetal 04:48.670 --> 04:51.190 wastage in this pre clinical group, 04:51.190 --> 04:51.770 if you will, 04:51.770 --> 04:53.280 is really quite high. 04:53.770 --> 04:54.010 Now, 04:54.010 --> 04:56.100 it's important to remember, 04:56.100 --> 04:58.610 as we discuss in more detail the genetics of 04:58.610 --> 04:59.980 spontaneous abortion, 05:00.250 --> 05:02.740 that what we're talking about here are embryos that are 05:02.740 --> 05:04.310 morphological e abnormal, 05:04.320 --> 05:07.010 and the ones that are left might still 05:07.010 --> 05:09.950 have a gross change in the chromosome number of their 05:09.950 --> 05:10.680 structure. 05:10.690 --> 05:11.240 Uh, 05:11.250 --> 05:13.980 they might well have a mutant gene that which 05:13.990 --> 05:16.510 which would have conferred lethality later on. 05:16.520 --> 05:19.480 Or they could have had apologetic mechanism that would 05:19.480 --> 05:21.240 have produced a malformation. 05:21.240 --> 05:22.080 So if you will, 05:22.090 --> 05:24.860 we start with the fact that this is the incidence of 05:24.870 --> 05:25.890 fetal wastage. 05:25.890 --> 05:28.850 And then we go to some more specific areas that are more 05:28.850 --> 05:31.090 amenable to clinical diagnosis. 05:31.260 --> 05:34.210 Now it's known 05:34.220 --> 05:34.880 um, 05:34.890 --> 05:35.970 to most of us, 05:35.980 --> 05:36.320 uh, 05:36.330 --> 05:38.970 hopefully all of us That the incidence of 05:38.970 --> 05:41.610 spontaneous abortion in the first trimester is 05:41.610 --> 05:43.870 around 12-15%. 05:43.880 --> 05:46.340 This is a fairly common figure. 05:46.360 --> 05:49.260 It tends to hold up from country to country from 05:49.260 --> 05:51.510 center to center and seems to be 05:51.520 --> 05:52.570 about, 05:52.580 --> 05:55.560 it seems to be a fairly reliable figure that we can remember. 05:56.240 --> 05:58.910 There's been a lot of controversy over the years about the 05:58.910 --> 06:01.070 ideology of spontaneous abortion. 06:01.080 --> 06:04.000 And if this were the late 50s 06:04.000 --> 06:04.770 and I were up here, 06:04.770 --> 06:07.670 we would have to play homage to the theory of poor 06:07.680 --> 06:09.510 steroid of genesis in the placenta. 06:09.520 --> 06:10.040 Uh, 06:10.050 --> 06:11.030 but by and large, 06:11.030 --> 06:13.650 I think this probably has fewer advocates that it might 06:13.650 --> 06:14.620 have uh, 06:14.630 --> 06:15.950 in the past, 06:16.240 --> 06:18.740 hopefully no endocrine spies in the audience 06:19.140 --> 06:21.550 when chromosomes became readily 06:21.550 --> 06:24.550 available for to the uh to to 06:24.550 --> 06:27.260 be applied to spontaneous aborts is it 06:27.260 --> 06:30.160 became apparent that a very large percent 06:30.170 --> 06:31.450 of spontaneous aborts, 06:31.450 --> 06:33.600 his head chromosomal abnormalities. 06:33.600 --> 06:36.520 And the next slide uh reminds us the 06:36.520 --> 06:37.350 next slide, 06:38.540 --> 06:40.330 subtle hints do wonders. 06:40.530 --> 06:43.490 The next slide reminds us that about 40 06:43.490 --> 06:46.020 to 50% of all spontaneous 06:46.020 --> 06:48.720 aborts is are chromosomally abnormal. 06:48.730 --> 06:51.640 Uh Now I put the other categories, 06:51.640 --> 06:54.250 mutant genes and apologetic disorders, 06:54.340 --> 06:57.140 to remind us that we really don't know anything at all 06:57.140 --> 06:59.720 about the role of mutant genes or apologetic 06:59.720 --> 07:02.460 mechanisms in causing spontaneous abortions. 07:02.470 --> 07:03.350 However, 07:03.350 --> 07:04.800 if on the other side, 07:04.800 --> 07:05.500 for example, 07:05.500 --> 07:08.110 if we were to extend this slide and to ask 07:08.110 --> 07:11.000 ourselves what is the extent of the incidences 07:11.010 --> 07:13.560 of such abnormalities in the newborn population? 07:13.940 --> 07:16.920 We'd find that the figures from top to bottom would be about 07:16.920 --> 07:19.030 0.5%, 07:19.320 --> 07:20.150 and 1%. 07:20.540 --> 07:22.960 That is only chromosomal abnormalities, 07:22.960 --> 07:23.520 makeup. 07:23.530 --> 07:23.730 Oh, 07:23.730 --> 07:26.650 perhaps 1/4 of all of the congenital 07:26.650 --> 07:29.440 abnormalities that one would prospectively detect in the 07:29.440 --> 07:30.440 newborn nursery. 07:30.440 --> 07:33.160 That's a that's a minimum figure of the 2%. 07:33.840 --> 07:36.800 So that uh this is only one 07:36.810 --> 07:39.600 of several genetic mechanisms among equals, 07:39.600 --> 07:42.520 if you will in causing malformations and yet it 07:42.520 --> 07:44.970 happens to be the only one that we can look at in the 07:44.970 --> 07:47.050 spontaneous abortion population. 07:47.060 --> 07:50.000 And I would armchairs and submit that 07:50.010 --> 07:52.710 uh looking at such data and 07:52.710 --> 07:55.060 extrapolating to the newborn population, 07:55.070 --> 07:58.010 it's logical to deduce that the vast majority of 07:58.010 --> 07:58.780 first trimester, 07:58.780 --> 08:01.760 spontaneous aborts is probably results 08:01.760 --> 08:03.050 from a genetic mechanism. 08:03.060 --> 08:05.810 We know that about half a chromosomally abnormal. 08:05.820 --> 08:08.640 Uh It's certainly logical that others could result from 08:08.640 --> 08:11.230 gene mutations of the type we mentioned simple 08:11.230 --> 08:14.170 mandolin inheritance and from polytechnic types 08:14.170 --> 08:15.220 of mechanisms. 08:15.350 --> 08:15.620 Now, 08:15.620 --> 08:17.820 if we look at the chromosomal abnormalities, 08:17.830 --> 08:18.760 next slide, 08:20.140 --> 08:21.030 we notice, 08:22.440 --> 08:23.380 try to focus, 08:23.650 --> 08:26.120 we notice that the incidents 08:26.130 --> 08:28.940 the I can't tell whether it's 08:28.940 --> 08:29.370 focused, 08:29.370 --> 08:31.500 but it doesn't seem to be a little better. 08:31.500 --> 08:31.950 Thank you. 08:33.040 --> 08:35.830 Uh It's interesting that the spectrum of 08:35.830 --> 08:38.770 these anomalies is vastly different from what one 08:38.770 --> 08:40.430 would see in the newborn nursery. 08:40.440 --> 08:41.040 For example, 08:41.040 --> 08:42.230 on the right side of the column, 08:42.230 --> 08:44.580 you can look at the prevalence of abnormal 08:44.590 --> 08:46.970 chromosomal abnormalities in all 08:46.970 --> 08:49.080 conceptions and on the left, 08:49.080 --> 08:51.940 you can see the prevalence is and spontaneous abortions 08:52.020 --> 08:54.950 as dr Goebbels has eluded the vast majority 08:54.950 --> 08:57.910 of of uh of our 08:57.910 --> 09:00.420 chromosomal abnormalities that occur in the live born 09:00.420 --> 09:03.190 population that tend to be auto 09:03.190 --> 09:05.930 soma trisomy or more expressly, 09:05.930 --> 09:08.500 in fact making up the largest portion sex chromosome. 09:08.500 --> 09:10.700 Apollo sex chromosome a. 09:10.700 --> 09:11.080 Policy. 09:11.080 --> 09:13.090 So me X xy males, 09:13.100 --> 09:14.530 xy Y males and X. 09:14.530 --> 09:14.810 X. 09:14.810 --> 09:15.720 Females. 09:15.730 --> 09:18.480 It's really relatively rare to 09:18.480 --> 09:21.160 find prospectively of 45 X female. 09:21.160 --> 09:21.630 In fact, 09:21.630 --> 09:24.010 the prevalence is only about one in every 3000 09:24.010 --> 09:24.970 females. 09:24.980 --> 09:27.790 Uh It's likewise extraordinary rare to 09:27.790 --> 09:30.580 find a trip Lloyd or Tetra employed as Dr Goebbels has 09:30.580 --> 09:31.080 mentioned. 09:31.110 --> 09:33.870 Yet if we look in the spontaneous abortion 09:33.870 --> 09:34.640 population, 09:34.640 --> 09:37.430 we find that these abnormalities make up 09:37.440 --> 09:39.460 a relatively large proportion. 09:39.470 --> 09:40.600 For example, 09:40.600 --> 09:43.560 7% of all chromosomally 09:43.560 --> 09:46.470 abnormal spontaneous abortions turned out to have a 09:46.470 --> 09:47.860 45 X compliment. 09:48.940 --> 09:49.450 Um, 09:50.240 --> 09:50.510 No, 09:50.510 --> 09:50.990 I'm sorry, 09:50.990 --> 09:53.830 7% of all spontaneous abortions have a 45 09:53.830 --> 09:54.830 x compliment. 09:54.840 --> 09:57.450 About 20% of the chromosomally 09:57.450 --> 09:58.030 abnormal. 09:58.030 --> 09:59.870 A vortices have such a compliment. 09:59.880 --> 10:00.660 Likewise, 10:00.660 --> 10:02.930 we can see that auto some will try. 10:02.930 --> 10:05.300 Somebody represents a relatively high 10:05.300 --> 10:06.050 proportion. 10:06.320 --> 10:08.600 And in fact if we wanted to clear up the slide, 10:08.600 --> 10:11.260 we could break that down and prove to you 10:11.440 --> 10:12.540 that it's trisomy, 10:12.540 --> 10:14.010 not simply for 13, 10:14.020 --> 10:16.770 18 and 21 is one detecting the live 10:16.770 --> 10:17.820 born population, 10:17.840 --> 10:20.380 but rather for practically any autism in the 10:20.380 --> 10:21.160 compliment. 10:21.300 --> 10:22.120 Likewise, 10:22.130 --> 10:25.100 Trip Lloyd constitutes about 8% of 10:25.100 --> 10:26.570 spontaneous abortions. 10:26.740 --> 10:29.450 Tetra ploiesti about 2% of spontaneous 10:29.450 --> 10:30.090 abortions, 10:30.100 --> 10:33.070 so that we're really dealing with fairly high prevalence is 10:33.070 --> 10:34.230 that these disorders. 10:34.290 --> 10:37.240 Yet many of these are extraordinarily 10:37.240 --> 10:37.640 rare, 10:37.640 --> 10:39.510 are not detected at all in the, 10:39.520 --> 10:41.170 in the live born population. 10:41.420 --> 10:44.290 This is yet another indication of some of the mechanisms 10:44.290 --> 10:46.150 that take place in biology, 10:46.160 --> 10:46.630 uh, 10:46.640 --> 10:49.370 to select against embryos that have not 10:49.380 --> 10:51.760 developed normally up until that period of time. 10:52.430 --> 10:52.860 Now, 10:53.540 --> 10:54.270 unfortunately, 10:54.270 --> 10:56.720 we're rarely going to have the availability of 10:56.720 --> 10:57.930 spontaneous abortion. 10:57.930 --> 11:00.460 Certainly we can't pull the hospital charge from 11:01.040 --> 11:01.620 Uh, 11:01.630 --> 11:04.340 20 years ago or 10 years ago or three 11:04.340 --> 11:07.000 months ago for most hospitals and know what the 11:07.000 --> 11:09.860 compliment is of of a spontaneous 11:09.860 --> 11:10.440 abortion. 11:10.450 --> 11:13.450 So I think in terms of counseling and giving you some 11:13.450 --> 11:15.470 practical advice to tell to patients, 11:15.470 --> 11:17.410 we should start with first of all, 11:17.410 --> 11:19.920 a series of patients who have had spontaneous 11:19.920 --> 11:22.600 abortion and asked what's the recurrence risk? 11:22.610 --> 11:23.660 And the next slide, 11:24.040 --> 11:26.330 I hope starts us off on that. 11:26.330 --> 11:27.360 And indeed it does. 11:28.040 --> 11:28.960 If you could focus it. 11:30.040 --> 11:32.970 Uh this these data are collected 11:32.970 --> 11:35.860 by Warburton and fraser and uh 11:36.440 --> 11:39.040 The early 1960s at McGill. 11:39.050 --> 11:41.550 And they have held up in many other places. 11:41.550 --> 11:44.490 And they simply remind us of the risk 11:44.490 --> 11:47.200 of recurrence of spontaneous abortion 11:47.200 --> 11:49.850 following X numbers of previous 11:49.850 --> 11:50.460 abortion. 11:50.470 --> 11:53.030 You can see the uh population 11:53.030 --> 11:55.900 risk uh if mother had undergone no 11:55.900 --> 11:57.700 spontaneous abortions was around 11:57.700 --> 11:59.110 12%, 11:59.470 --> 12:00.860 in some other figures. 12:00.870 --> 12:03.470 And to the right or the risk figures after 12:03.470 --> 12:06.020 123 and even four spontaneous 12:06.020 --> 12:08.060 abortions have taken place. 12:08.340 --> 12:10.760 There are relatively few in the 12:10.840 --> 12:11.580 Uh, 12:11.590 --> 12:14.230 four category and that may explain the 12:14.240 --> 12:16.040 slight drop in incidences. 12:16.040 --> 12:16.950 But by and large, 12:16.950 --> 12:19.390 we're talking about a 25% 12:19.390 --> 12:22.370 risk and this is a ballpark figure that I use 12:22.370 --> 12:23.810 if someone asked me, 12:23.810 --> 12:26.400 what's the risk of recurrence after one or two 12:26.400 --> 12:26.940 figures, 12:26.950 --> 12:29.590 25% are buying is by and large. 12:29.590 --> 12:30.960 The figures that we look at. 12:31.440 --> 12:32.010 Uh, 12:32.020 --> 12:34.830 this doesn't seem to vary a great 12:34.830 --> 12:37.190 deal depending upon maternal age or, 12:37.200 --> 12:40.090 or depending upon several other factors that we might 12:40.100 --> 12:40.980 take place. 12:41.180 --> 12:43.890 I remind you that we're talking about first trimester 12:43.890 --> 12:44.440 abortions, 12:44.440 --> 12:45.900 second trimester abortions. 12:45.900 --> 12:48.660 I don't need to tell this group or ideologically 12:48.660 --> 12:49.550 distinct, 12:49.560 --> 12:50.680 such things as as, 12:50.690 --> 12:53.470 as uterine anomalies and the likes of this and they 12:53.480 --> 12:55.770 tend to fall into different category and 12:55.780 --> 12:58.650 correspondingly have a slightly higher risk. 12:59.240 --> 12:59.500 Uh, 12:59.510 --> 13:01.540 I might point out here that, 13:01.550 --> 13:01.830 uh, 13:01.840 --> 13:04.500 in case there's anyone who has been asleep for the last 20 13:04.500 --> 13:05.210 years, 13:05.220 --> 13:05.740 that, 13:05.750 --> 13:06.350 uh, 13:06.360 --> 13:09.110 the previous figures were that after three 13:09.120 --> 13:10.370 spontaneous abortions, 13:10.370 --> 13:13.220 the risk for any subsequent abortion was about 13:13.230 --> 13:14.470 80-90%. 13:14.470 --> 13:17.150 And this is really the origin of the term 13:17.240 --> 13:18.550 of habitual abortion. 13:18.560 --> 13:21.430 I suspect now that there's probably, 13:21.440 --> 13:21.890 uh, 13:21.900 --> 13:24.750 no biological justification for using such a 13:24.750 --> 13:25.270 term. 13:25.280 --> 13:25.820 Uh, 13:25.830 --> 13:28.760 it might be in a convenient administrative tool 13:28.760 --> 13:31.760 to determine when one might determine one 13:31.760 --> 13:32.150 might, 13:32.160 --> 13:32.450 uh, 13:32.460 --> 13:33.600 study such couples, 13:33.600 --> 13:36.220 but it doesn't really have any biological meet. 13:36.230 --> 13:37.410 Uh, 13:37.420 --> 13:38.500 it's interesting, 13:38.510 --> 13:38.830 uh, 13:38.840 --> 13:41.150 that genetically along these lines, 13:41.440 --> 13:43.960 That about five of 13:43.960 --> 13:46.290 couples who have had three or more 13:46.290 --> 13:48.980 spontaneous abortions will turn out to have a 13:48.980 --> 13:51.420 balanced translocation in one of the other 13:51.420 --> 13:52.010 parent. 13:52.100 --> 13:54.830 And this might then this offers an explanation in 13:54.830 --> 13:57.520 these families as to why spontaneous 13:57.520 --> 14:00.190 abortion occurred in such families. 14:00.200 --> 14:02.480 It's very often wise to take a good 14:02.480 --> 14:04.500 pedigree in several generations, 14:04.500 --> 14:06.420 particularly the maternal side of the family. 14:06.430 --> 14:09.410 And see whether or not there are other individuals in 14:09.410 --> 14:12.090 whom spontaneous abortions or malformations have 14:12.090 --> 14:12.650 occurred. 14:12.860 --> 14:15.620 This would increase your risk although uh 14:15.630 --> 14:17.830 still uh if the data were negative, 14:17.830 --> 14:20.650 not necessarily be a reason for not performing the study. 14:21.340 --> 14:21.460 Now, 14:21.460 --> 14:22.660 what happens next slide? 14:23.640 --> 14:26.120 Uh If we did have the availability of 14:26.120 --> 14:28.960 chromosomal studies prior to counseling 14:28.960 --> 14:29.710 such families, 14:29.710 --> 14:32.660 these data are are scanning and they're from 14:32.660 --> 14:34.100 the boueiz in paris. 14:34.110 --> 14:36.550 And uh um 14:37.040 --> 14:39.120 at least based upon present indication, 14:39.120 --> 14:42.020 would suggest that the recurrence risk really doesn't vary a 14:42.020 --> 14:44.900 great deal depending upon whether or not the 14:44.910 --> 14:47.060 first to Boris's chromosomally abnormal, 14:47.060 --> 14:48.080 chromosomally normal, 14:48.080 --> 14:50.880 those data or not statistically significant. 14:50.890 --> 14:52.390 Uh interesting enough. 14:52.390 --> 14:52.850 However, 14:52.850 --> 14:55.600 next slide and tying in with some 14:55.600 --> 14:58.510 of dr Goldberg's comments that uh there 14:58.510 --> 15:01.270 does seem to be non random distribution of annual 15:01.270 --> 15:01.650 clarity. 15:01.650 --> 15:03.760 Chromosomal abnormalities in the population. 15:03.770 --> 15:06.230 Are these data and this are the boueiz, 15:06.240 --> 15:09.240 suggesting that if the first two borders was chromosomally 15:09.250 --> 15:10.280 normal, 15:10.300 --> 15:12.660 the second was also likely to be 15:12.840 --> 15:15.630 chromosomally normal and likewise that the 15:15.630 --> 15:16.650 first were abnormal, 15:16.650 --> 15:18.860 The second was more likely to be abnormal. 15:19.140 --> 15:21.740 The interesting point about this factor is that 15:21.750 --> 15:24.320 uh this suggests not only that the couple 15:24.470 --> 15:27.250 might have chromosomally abnormal aboard us, 15:27.280 --> 15:29.810 but it might also incidentally this one 15:29.810 --> 15:32.730 numerical abnormalities and not trance locations. 15:32.740 --> 15:35.420 Uh It also suggests that this couple might be at a 15:35.420 --> 15:38.310 relatively high risk for having a nonlethal 15:38.310 --> 15:39.670 chromosomal abnormalities. 15:39.670 --> 15:40.530 So that for example, 15:40.530 --> 15:43.440 if we could identify this group out from the 15:43.440 --> 15:46.310 largest pool of individuals who spontaneous 15:46.310 --> 15:49.300 aborts is well then this might be a 15:49.310 --> 15:52.240 couple than whom we might offer antenatal diagnosis 15:52.250 --> 15:54.610 even had they had no previously. 15:54.620 --> 15:57.430 Uh even if they do not 15:57.430 --> 16:00.210 confirm to one of the other indications that 16:00.210 --> 16:02.570 dr Goldberg's mentioned translocation previous. 16:02.580 --> 16:05.460 Try somebody or increased maternal age. 16:05.540 --> 16:07.460 Uh Next slide please. 16:08.240 --> 16:11.230 Now One would logically deduce that if 16:11.230 --> 16:13.710 the incidents of chromosomal abnormalities in the first 16:13.710 --> 16:15.960 trimester borders population is 16:15.970 --> 16:18.060 50% and therefore 16:18.070 --> 16:20.990 uh there's a selection occurring that 16:20.990 --> 16:23.340 if we move further along the line in 16:23.350 --> 16:25.800 particular to the stillborn population, 16:25.810 --> 16:28.580 we might find also in incidents that's 16:28.580 --> 16:31.260 higher than in the newborn population. 16:31.440 --> 16:34.430 You recall once again that about one in every 200 16:34.440 --> 16:36.760 live-born births has a chromosomal abnormality. 16:37.340 --> 16:37.640 Well, 16:37.640 --> 16:40.070 if we look at the stillbirth population, 16:40.740 --> 16:43.470 it was done in the study quoted from The Lancet, 16:43.940 --> 16:45.970 you can see how long the top line 16:48.340 --> 16:51.240 Uh that about 9% of ante 16:51.240 --> 16:53.170 partum macerated stillbirth. 16:53.180 --> 16:55.850 Stillborn infants have a chromosomal abnormality. 16:56.000 --> 16:58.980 The hitch here is that they were only able to successfully culture about 16:58.990 --> 17:00.160 20% of these. 17:00.240 --> 17:03.110 If you look at the intra partum uh stillbirths 17:03.110 --> 17:05.570 with a correspondingly increased success rate in the 17:05.570 --> 17:06.310 cultures, 17:06.360 --> 17:09.090 they still got about a 4% incidents and 17:09.090 --> 17:10.920 likewise the early neonatal death, 17:10.920 --> 17:12.650 this shouldn't surprise anyone. 17:12.710 --> 17:14.260 Likewise was high. 17:14.640 --> 17:17.630 The next slide shows us that if we break this 17:17.630 --> 17:20.000 down further into the type of 17:20.000 --> 17:22.020 abnormality and in particular 17:22.020 --> 17:24.980 exclude the central nervous system anomalies 17:24.980 --> 17:26.520 and essentially spina bifida, 17:26.530 --> 17:29.350 which can be diagnosed by alfa alfa 17:29.350 --> 17:30.490 feta protein. 17:30.500 --> 17:33.460 Wind finds really a quite high incidence of chromosomal 17:33.460 --> 17:36.170 abnormalities in this stillborn population. 17:36.340 --> 17:38.070 So this is yet another indication. 17:38.070 --> 17:40.390 I think that nature is selecting 17:40.390 --> 17:43.370 against abnormal offspring at 17:43.370 --> 17:46.140 a number of places in the 17:46.150 --> 17:47.880 preimplantation stage, 17:47.890 --> 17:50.700 in the early implantation of blastocyst 17:50.700 --> 17:51.430 stage. 17:51.440 --> 17:54.180 Uh And in addition in the 17:54.180 --> 17:56.090 clinically recognized pregnancies, 17:56.090 --> 17:58.860 and finally immediately prior to birth. 17:58.870 --> 18:01.740 Uh really a very nice, 18:01.750 --> 18:04.270 very nice picture in terms of its steely ology. 18:04.940 --> 18:06.150 Let's turn on, 18:06.160 --> 18:07.360 turn the slide off please. 18:07.940 --> 18:10.890 Now we're really late for time and I 18:10.890 --> 18:12.150 don't want to hold us up too much. 18:12.150 --> 18:15.020 But I like to point out uh I'm closing this 18:15.020 --> 18:15.390 morning. 18:15.390 --> 18:18.200 About three or four major areas in which common 18:18.200 --> 18:20.900 heritable heritable factors exist 18:20.910 --> 18:21.330 in, 18:21.340 --> 18:23.920 if you will very common disorders and 18:23.920 --> 18:26.790 obstetrics and gynecology that we attend to 18:26.790 --> 18:29.340 see on a day to day basis. 18:29.340 --> 18:32.190 And we could really divide this into a number 18:32.190 --> 18:33.280 of different disorders. 18:33.280 --> 18:36.040 The first of all are the apologetic mechanisms and the next 18:36.040 --> 18:38.170 slide shows you 18:40.740 --> 18:41.810 if you could focus that. 18:41.820 --> 18:44.490 Thank you today to that I alluded to before. 18:44.500 --> 18:47.470 And I suspect that if we looked at a lot of different 18:47.470 --> 18:50.230 common guo and variables a conjugal diagonal 18:50.230 --> 18:50.990 for you any, 18:51.000 --> 18:51.910 anything you want to, 18:51.910 --> 18:53.230 the prevalence of my illness, 18:53.230 --> 18:53.960 for example, 18:53.970 --> 18:55.890 we would find data such as this. 18:55.890 --> 18:58.860 The point of fact is that very few people have looked 18:58.860 --> 19:01.490 at them and uh therefore we tend to 19:01.490 --> 19:03.120 think that they don't exist. 19:03.120 --> 19:03.800 But for example, 19:03.800 --> 19:06.760 look at the age the mean differences in the ages 19:06.760 --> 19:09.240 of monarchy between these different 19:09.240 --> 19:09.940 relatives. 19:09.980 --> 19:11.370 If you're identical twins, 19:11.370 --> 19:13.190 a series of 51 patients, 19:13.200 --> 19:14.270 uh, 19:14.280 --> 19:16.770 the mean difference in their age of monarchy is 2.8 19:16.770 --> 19:17.310 months, 19:17.360 --> 19:18.530 not identical twins, 19:18.530 --> 19:21.300 12 months subs 12.9 19:21.300 --> 19:21.640 months. 19:21.640 --> 19:24.590 The fact that this and this were almost 19:24.590 --> 19:27.290 identical to suggest that the genetic components 19:27.300 --> 19:30.270 are fairly play a relatively large role 19:30.270 --> 19:31.880 in determining the age of monarchy. 19:32.170 --> 19:33.060 Likewise mother, 19:33.060 --> 19:36.040 daughter and other combination so that I 19:36.040 --> 19:38.930 suspect that we can take the age of monarchy as a general 19:38.930 --> 19:39.670 indication. 19:39.700 --> 19:40.730 And for example, 19:40.730 --> 19:42.960 I've used this also uh to 19:42.960 --> 19:45.750 determine the ages of menopause. 19:45.760 --> 19:48.750 And very often I'm confronted with a situation in 19:48.750 --> 19:51.330 which the age of many of the age of 19:51.340 --> 19:54.290 expected menopause might change the way we 19:54.290 --> 19:55.720 might manage a patient. 19:55.730 --> 19:58.580 And it's uh at least find it 19:58.580 --> 20:01.580 comforting to ask what the age of menopausal might 20:01.580 --> 20:01.780 be. 20:01.780 --> 20:02.300 For example, 20:02.300 --> 20:04.820 if we're contemplating uh particular 20:04.820 --> 20:07.760 operation safe from my Omagh's on a patient 20:07.760 --> 20:10.640 who's 46 demonstrating the fact 20:10.640 --> 20:13.250 that she had other maternal relatives and 20:13.250 --> 20:16.020 sibs who underwent their menopause at 47 20:16.090 --> 20:18.910 might uh tend to make me a little 20:18.910 --> 20:20.280 hesitant in doing the procedure. 20:20.280 --> 20:23.050 Whereas if everyone else told me that they underwent their 20:23.050 --> 20:25.860 menopause and their family at age 59 or age 20:25.860 --> 20:28.770 60 that suggests that we might be a 20:28.770 --> 20:31.170 little less likely to ride out the situation 20:32.130 --> 20:34.650 now in the area of infertility. 20:34.660 --> 20:35.450 Next slide. 20:37.540 --> 20:37.830 you know, 20:37.840 --> 20:38.950 just turn that one off. 20:41.340 --> 20:43.090 Could you back thank you. 20:43.130 --> 20:46.010 In the age of in in the area of infertility genetics 20:46.010 --> 20:49.000 plays a very large role in lots of situations. 20:49.000 --> 20:51.340 And we're going to allude to these tomorrow morning with DR. 20:51.340 --> 20:53.150 Goebbels discusses gunbattles, 20:53.150 --> 20:55.770 genesis and I cover uh some forms of 20:55.770 --> 20:57.510 genital ambiguity. 20:57.520 --> 21:00.230 There are three areas that that in which heritable 21:00.230 --> 21:02.890 factors have definitely been identified. 21:02.890 --> 21:05.830 And at least at least like to mention them because I think 21:05.830 --> 21:06.570 that they're worth. 21:06.570 --> 21:09.120 You're asking in terms of general histories. 21:09.120 --> 21:11.720 The first of these are military infusion anomalies, 21:11.730 --> 21:14.550 uh incomplete fusion defects by Cornthwaite 21:14.550 --> 21:14.870 uterus. 21:14.870 --> 21:15.780 The likes of this. 21:15.790 --> 21:17.330 Uh If I cared to, 21:17.330 --> 21:19.920 I could cite at least a dozen cases in which 21:19.920 --> 21:22.760 multiple sibs or females and 21:22.770 --> 21:25.710 more than one generation appeared to have 21:25.710 --> 21:27.080 such abnormalities. 21:27.090 --> 21:30.080 Uh the most likely mechanism for these 21:30.080 --> 21:32.430 situations is that we're looking at apologetic or 21:32.430 --> 21:34.910 multifactorial inheritance and the 21:34.920 --> 21:36.060 recurrence risk. 21:36.060 --> 21:38.960 Then if we were asked to uh Pro for 21:38.960 --> 21:40.960 that might be in the range of 5%. 21:40.960 --> 21:43.730 Now that's getting pretty shaky and I would prefer not to give a 21:43.730 --> 21:45.880 recurrence risk for such a thing. 21:45.930 --> 21:47.220 But you've pressed the wall. 21:47.220 --> 21:48.650 That's probably what I'd say, 21:48.660 --> 21:51.400 not only because it is an abnormality of a 21:51.400 --> 21:52.740 single organ system, 21:52.780 --> 21:55.290 but because there are heritable tendencies that have been 21:55.290 --> 21:57.740 demonstrated second area uh 21:57.750 --> 22:00.700 disorder that we often come across for 22:00.700 --> 22:03.040 which proven probably apologetic 22:03.050 --> 22:05.930 conditions can can be demonstrated as 22:05.930 --> 22:07.060 endometriosis. 22:07.340 --> 22:07.930 Again, 22:07.930 --> 22:10.720 we could quote five or six cases in which four or 22:10.720 --> 22:12.140 more Sibs have been affected. 22:12.140 --> 22:14.970 A number of instances in which a 22:14.970 --> 22:17.520 mother and her multiple affected Sibs had been 22:17.520 --> 22:18.110 affected. 22:18.200 --> 22:21.030 The third areas Leventhal syndrome, 22:21.040 --> 22:23.770 there's at least one excellent article from Memphis 22:23.770 --> 22:26.660 group in The Great Journal about three or four years ago. 22:26.840 --> 22:29.790 That suggests that Stein Leventhal syndrome may indeed be an 22:29.800 --> 22:31.360 excellent dominant disorder. 22:31.640 --> 22:34.410 I don't think there's any question but that there are inheritable 22:34.410 --> 22:37.250 tendencies uh for Stein Leventhal syndrome, 22:37.250 --> 22:39.900 but the exact mode of transmission is 22:39.900 --> 22:40.480 still, 22:40.490 --> 22:41.000 I think, 22:41.010 --> 22:43.960 open to question the final group that 22:43.960 --> 22:45.860 I might mention our next slide, 22:46.240 --> 22:48.650 some of the heritable factors in G. 22:48.650 --> 22:48.820 Y. 22:48.820 --> 22:48.990 N. 22:48.990 --> 22:49.780 Cancers. 22:49.790 --> 22:52.380 Uh I hasten to add that 22:52.390 --> 22:55.270 uh I wouldn't recognize left notify 22:55.270 --> 22:57.730 tripped across it on the stage on the way out, 22:57.740 --> 23:00.360 but it's important to recognize that many of these 23:00.370 --> 23:02.920 cancers are indeed heritable in 23:02.920 --> 23:03.820 particular. 23:03.830 --> 23:05.360 Three for three, 23:05.360 --> 23:07.730 there seemed to be relatively few 23:07.730 --> 23:10.100 indications of any type of heritability. 23:10.280 --> 23:13.260 There's not much known about vulvar and and and 23:13.270 --> 23:15.730 and vaginal cancer in terms of their genetics, 23:15.770 --> 23:18.620 but there have been substantial studies and cervical 23:18.620 --> 23:20.000 cancers and really, 23:20.000 --> 23:22.710 almost no indication of a heritable tendency. 23:22.920 --> 23:25.680 This to me would strengthen the hypothesis that 23:25.680 --> 23:28.150 herpes virus was an ideological 23:28.150 --> 23:28.840 factor. 23:28.910 --> 23:30.770 And it was uh, 23:30.780 --> 23:31.610 hitting in a, 23:31.620 --> 23:34.560 in a more or less random fashion in the general population 23:34.560 --> 23:36.030 with no group, 23:36.040 --> 23:37.640 particular pre predisposed, 23:37.640 --> 23:40.380 except no group predisposed prior to whatever 23:40.380 --> 23:43.290 socioeconomic factors put them in the high 23:43.290 --> 23:44.240 risk category. 23:44.300 --> 23:47.030 It's interesting that that vulvar 23:47.030 --> 23:49.980 cancers and occasionally vaginal 23:49.980 --> 23:52.530 cancers have also been uh, 23:52.540 --> 23:55.380 a relation has been suggested with herpes in 23:55.380 --> 23:57.690 this group here for a number of the other 23:57.690 --> 23:58.580 disorders. 23:58.590 --> 24:01.150 There are clearly heritable tendencies that I think are worth 24:01.150 --> 24:03.810 remembering about and are worth asking questions 24:03.810 --> 24:04.700 about uh, 24:04.710 --> 24:06.540 endometrial carcinoma. 24:06.550 --> 24:07.430 Uh, 24:07.440 --> 24:10.440 sometimes in association with adenocarcinoma 24:10.450 --> 24:11.840 of other systems in particular, 24:11.840 --> 24:14.390 the colon Have been reported to be heritable. 24:14.390 --> 24:17.220 In the number of instances there could be two reasons. 24:17.220 --> 24:17.860 # one, 24:17.860 --> 24:20.320 it may be that we're looking at the indirect 24:20.330 --> 24:23.240 uh fact that patients who 24:23.240 --> 24:25.710 develop endometrial carcinoma are more likely to be 24:25.710 --> 24:28.560 obese have hypertension and diabetes and the 24:28.560 --> 24:30.650 latter to certainly have heritable tendencies. 24:30.660 --> 24:32.560 So this could be indirect. 24:32.640 --> 24:33.710 On the other hand, 24:33.710 --> 24:36.420 there may be a given subset of patients with 24:36.420 --> 24:38.780 endometrial carcinoma who have 24:38.990 --> 24:41.540 a demonstrable genetic basis 24:42.040 --> 24:44.920 in the ovarian epithelial cancers serious 24:44.920 --> 24:45.560 mutinous. 24:45.570 --> 24:48.310 Uh at least those are the only two for which good 24:48.310 --> 24:49.330 data are available. 24:49.340 --> 24:49.800 Uh, 24:49.810 --> 24:52.650 There are unequivocally good half dozen 24:52.650 --> 24:54.850 families in which multiple 24:55.040 --> 24:57.080 Individuals in multiple generations, 24:57.080 --> 24:58.380 four or five generations, 24:58.380 --> 25:01.070 sometimes as many as 20 and 25 affected 25:01.070 --> 25:01.660 individuals. 25:01.660 --> 25:04.360 And the kindred will have ovarian epithelial 25:04.740 --> 25:06.880 varying the alert carcinomas. 25:06.890 --> 25:07.910 Uh, 25:07.920 --> 25:10.630 one would predict incidentally from other 25:10.630 --> 25:13.280 models and cancer that heritable cancers 25:13.290 --> 25:15.860 tend to more likely be bilateral 25:15.930 --> 25:18.520 and more likely to appear at a relatively young 25:18.530 --> 25:19.310 age. 25:19.320 --> 25:22.250 I've just recently reviewed these days an attempt 25:22.250 --> 25:24.860 to come up with such heterogeneity and really haven't 25:24.870 --> 25:26.800 haven't confirmed that here. 25:26.800 --> 25:29.670 But I think that's something we can look for in the future. 25:30.280 --> 25:31.080 Terror thomas. 25:31.090 --> 25:32.370 But I insisted terry thomas, 25:32.370 --> 25:34.960 turmoil cyst one first of all might 25:34.970 --> 25:37.720 expect a heritable tendency based upon the 25:37.730 --> 25:40.550 relatively high prevalence of bilateral itty. 25:40.550 --> 25:43.280 This is something that have been detected for 25:43.290 --> 25:46.110 other heritable tumors like retinoblastoma and 25:46.110 --> 25:46.800 Wilms tumor, 25:46.800 --> 25:48.870 which pediatric tumors for example, 25:49.000 --> 25:51.440 we know we all know that Durham boys tend to be 25:51.450 --> 25:54.400 bilateral in varying percentage depending 25:54.400 --> 25:57.270 upon what textbook and what month you read. 25:57.280 --> 25:59.660 But any rate certainly heritable tendencies, 25:59.670 --> 26:02.520 interestingly it's now been shown that 26:02.530 --> 26:05.190 uh terra toma is in the ovary 26:05.190 --> 26:07.850 probably were result from parthenogenesis 26:07.850 --> 26:09.880 because using the same G six Pd 26:09.880 --> 26:10.870 principles, 26:10.880 --> 26:13.820 if one takes uh looks at the G. 26:13.820 --> 26:14.170 C. 26:14.240 --> 26:16.940 G six pd types off terry 26:16.940 --> 26:19.290 thomas and mothers who are hetero zygotes. 26:19.290 --> 26:21.930 You find that it's all of one type of the other which 26:21.930 --> 26:24.770 indicates that it's probably occurring at a 26:24.770 --> 26:27.490 very early age and probably resulting 26:27.490 --> 26:29.780 from poorly formed over this 26:29.790 --> 26:31.260 quote unquote. 26:31.270 --> 26:34.200 And let's not get into that any further arena 26:34.200 --> 26:36.960 blast omagh's or certainly lighting cell tumors. 26:36.980 --> 26:39.340 Again enough 26:39.350 --> 26:42.280 examples of familial tumors that it's probably worth 26:42.280 --> 26:44.960 considering granule also cell tumors. 26:44.960 --> 26:45.800 In general, 26:45.800 --> 26:48.090 one does not find any heritable tendencies. 26:48.100 --> 26:48.790 However, 26:48.790 --> 26:50.170 the pukes Jaeger syndrome, 26:50.170 --> 26:53.000 which is autism dominant syndrome in which one 26:53.000 --> 26:55.590 gets oral melanocytes along the 26:55.590 --> 26:58.410 lips as well as colonic polyp Asus 26:58.420 --> 27:01.290 has associated with it fully. 27:01.300 --> 27:04.190 About a 25% prevalence rates for granular 27:04.190 --> 27:05.320 cell cell tumors. 27:05.350 --> 27:08.280 So that these in general I think are some 27:08.280 --> 27:10.930 conditions that we might think about in 27:10.940 --> 27:11.310 G. 27:11.310 --> 27:11.470 Y. 27:11.470 --> 27:11.590 N. 27:11.590 --> 27:14.550 Disorders and uh in many cases 27:14.560 --> 27:16.180 particularly the territo hmas. 27:16.190 --> 27:19.070 Uh they're worth some prospective analysis and other 27:19.070 --> 27:21.890 relatives particular uh in multiple affected 27:21.890 --> 27:24.600 sibs uh We could talk about some other 27:24.600 --> 27:27.060 disorders like this but I think you get the picture 27:27.540 --> 27:30.330 uh And in general I close by saying the reason 27:30.340 --> 27:33.170 there are two good reasons why we haven't come 27:33.170 --> 27:34.880 up with more common G. 27:34.880 --> 27:35.080 Y. 27:35.080 --> 27:35.270 N. 27:35.270 --> 27:36.710 Disorders that are heritable. 27:36.800 --> 27:39.710 The first of these is that we're looking at an internal organ 27:39.710 --> 27:40.170 system. 27:40.180 --> 27:42.950 It's a lot easier to detect heritability in 27:42.950 --> 27:45.770 skin and eyes and nails and 27:45.840 --> 27:48.450 hands and the likes of that where we can call in all the 27:48.450 --> 27:51.120 relatives and send them around a big table 27:51.130 --> 27:53.970 uh and look at them and come up with a pedigree in 27:53.970 --> 27:56.260 the in a matter of minutes. 27:56.270 --> 27:59.230 Whereas it's obviously much more difficult when we're 27:59.230 --> 28:01.790 asking questions about endometriosis of the likes of 28:01.790 --> 28:02.270 that. 28:02.280 --> 28:05.270 And the second is that we're dealing with a sex limited 28:05.270 --> 28:05.830 system. 28:05.840 --> 28:08.410 Uh Let's say that we have for 28:08.410 --> 28:09.110 example, 28:09.300 --> 28:11.730 terra thomas are indeed although somewhat 28:11.730 --> 28:12.350 recessive, 28:12.840 --> 28:14.060 they don't think they are. 28:14.640 --> 28:15.930 Please don't quote me that way. 28:15.930 --> 28:17.400 But let's just say that they are. 28:17.760 --> 28:20.110 If we went about trying to find some familiar 28:20.110 --> 28:21.970 aggregates at random, 28:22.180 --> 28:25.150 the probability that the any subsequent progeny 28:25.150 --> 28:28.020 after a pro ban would be affected is really 28:28.020 --> 28:29.490 not one in four. 28:29.500 --> 28:32.310 It's one in four if both males and females were 28:32.310 --> 28:32.930 affected. 28:32.990 --> 28:35.610 But since the probability is only one into that, 28:35.610 --> 28:38.300 we have a female coming out of that and the 28:38.300 --> 28:40.240 probability is only one in eight. 28:40.240 --> 28:40.740 So in other words, 28:40.740 --> 28:43.620 one in eight for every female chances are only one and 28:43.620 --> 28:46.550 two that we're dealing with the female so that we're going 28:46.550 --> 28:49.430 to see fewer examples of familial aggregates even 28:49.490 --> 28:52.100 if a condition is inherited in a in a 28:52.100 --> 28:53.060 genetic fashion. 28:56.140 --> 28:58.830 This program was produced through the mobile 28:58.830 --> 29:00.760 facilities of the television branch, 29:01.140 --> 29:02.730 health Sciences Media Division, 29:03.060 --> 29:04.620 Academy of Health Sciences, 29:04.620 --> 29:07.410 United States Army for SAM Houston 29:07.410 --> 29:08.040 texas.