More than one genetic affliction within the same family:Two case reports
Divya Agarwal and Shubha R Phadke Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India - 226014 Email:shubharaophadke@gmail.com
Genetic disorders, though rare, are still responsible for 2-3% of babies having congenital or genetically-determined
abnormalities at birth. Rarer still is the possibility of more than one genetic disorder afflicting the same family. In spite of
that, such families do exist and it is important that clinicians focus not only on the prevention of known genetic disorders
in a family but also on screening for other common genetic disorders and prevention of these disorders in all
families.
1 Case 1
A twenty-six year old female patient was referred by a gynecologist for pre-conceptional genetic counseling because her
previous child had Down syndrome. Karyotype of the proband, which had been done previously, had shown Robertsonian
translocation 46,XX,t(13;21). The couple was advised to get their blood karyotypes done. Along with that, as advised to
all women who visit our medical genetics out patient department for preconception counseling or in the
early antenatal period, we advised beta thalassemia carrier screening for the couple. The wife was found to
be carrier of a balanced translocation, her karyotype being 45,XX,t(13;21) and the husband’s karyotype
was normal (46, XY). In addition, the couple found to be carriers for mutations in the HBB (beta globin)
gene, the wife being carrier of the IVS 1-5(G→C) mutation for beta thalassemia and the husband being
carrier of the HbE mutation. They were thus counseled about the risk of recurrence of Down syndrome and
the risk of occurrence of beta thalassemia in their offspring and the possibility of prenatal diagnosis was
also explained to them. The couple was also counseled regarding the importance of getting their extended
family members screened for both the balanced translocation and thalassemia mutations running in their
respective families. In line with the fair degree of understanding that the couple had acquired, three years
later, the consultand’s sister came to us with the concern of knowing the possibility of Down syndrome
or thalassemia in her unborn child. She was not found to be a carrier of thalassemia mutation but was
found to be carrying the balanced translocation (Fig 1). Amniocentesis and fetal karyotype was done for
her at 16 weeks of pregnancy after due counseling. Karyotype of the fetus was 45,t (13;21) i.e. the fetus
was carrying a similar balanced translocation as the mother. The family opted to continue the pregnancy.
Figure 1: Pedigree of family 1.
Later, the parents of the proband came back to us at 10 weeks of pregnancy, for prenatal diagnostic testing. Chorionic
villus sampling was done followed by karyotype of fetus and mutational analysis for beta thalassemia. The fetal karyotype
showed 44 autosomes and 2 sex chromosomes. DNA mutational analysis for beta thalassemia revealed that the fetus was a
carrier of the maternal beta thalassemia mutation. As the fetus was not affected with either Down syndrome or beta
thalassemia, the family opted to continue the pregnancy. Despite the rare situation of two genetic disorders being present
within these two related families, both the couples were able to have healthy children after appropriate counseling and
testing.
2 Case 2
A 28 year old woman presented to us at 6 weeks of gestation with history of a previous child being affected with
transfusion-dependent thalassemia. She had been referred for prenatal diagnosis for the same in context of the present
pregnancy. While talking to her 33-year old husband who had accompanied her to the OPD, it became apparent that
he had subnormal intelligence. On further evaluation it was found that he had developmental delay and
behavioral problems noticed since 3 years of age. He had never been to school, could not read, write or do
simple calculations though he could take care of himself and helped in all the household work. The family
history revealed presence of intellectual disability in the brother and maternal uncle and mild intellectual
disability with behavioral problems in the mother and maternal aunt (Fig 2). In light of this family history
suggestive of X linked inheritance, Fragile X syndrome was suspected. Southern Blot Analysis for Fragile X
revealed increased triplet repeats in the FMR1 gene confirming our provisional diagnosis. Meanwhile, DNA
mutation analysis of the HBB (beta globin) gene in the couple suggested that the husband was carrier for
mutation of HbE and the wife was carrier for the IVS1-5(G-C) mutation of beta thalassemia. Both the
mutations were confirmed in their previous affected child. So, there were 2 genetic disorders in this family,
both of whose molecular bases were confirmed and hence prenatal diagnosis could be provided. Regarding
intellectual disability, the family was counseled that the risk of fragile X in male offspring of the couple
is negligible and all female offspring will be carriers of the mutation for fragile X. Carriers have variable
severity of cognitive dysfunction that cannot be differentiated/ predicted by any DNA test. In this family
there were two carrier females with some degree of manifestations. Targeted mutation analysis in chorionic
villus sample collected at 11 completed weeks of pregnancy showed that the fetus was carrying both the
thalassemia and HbE mutations like their previous child. The family opted for termination of the pregnancy.
Figure 2: Pedigree of family 2.
3 Discussion
The first case emphasizes that the presence of a single disease should not divert attention from routine screening for other
common genetic disorders. Beta thalassemia screening is advisable for each and every couple that is planning for
childbirth because of the high carrier frequency of the disease in India.1 High performance liquid chromatography of
hemoglobin is an easy screening method for thalassemia which is widely available and the results of which are
easily interpretable. Also noticeable and to be highlighted in this case is the importance of extended family
screening for the already known genetic traits or diseases in the family. The second case again beautifully
illustrates the fact that although genetic disorders are rare in occurrence, presence of more than one genetic
disorder in the same family though less probable, is possible. With detailed and careful history, proper
clinical evaluation and appropriate testing such families can be recognized and provided with the right
course of medical action. It reiterates the fact that a family could have more than one genetic affliction and
therefore we, as clinicians, should be vigilant enough to offer genetic counseling and appropriate investigations
to the families at risk of a child with a serious genetic disorder or a disorder with handicap. These cases
also stress the importance of pre-pregnancy genetic counseling, pedigree drawing and use of molecular and
cytogenetic investigations for genetic counseling and prenatal diagnosis.2,3 This will only be possible with
awareness about genetic investigations and counseling amongst primary care physicians, pediatricians and
obstetricians.
References
1. Verma I C, et al. Indian J Med Res 2011; 134: 507-21.
2. Phadke S R, et al. Natl Med J India 2002; 15: 363.
3. Ranganath P and Phadke SR. Perinatology 2013; 14: 1-6.