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Implications of Hypertrophic Cardiomyopathy Transmitted by Sperm Donation

Maron BJ, Lesser JR, Schiller NB, Harris KM, Brown C, Rehm HL. JAMA. 2009;302:1681-4

In the above issue of JAMA, Maron et al. reported the clinical circumstances and implication of hypertrophic cardiomyopathy (HCM) transmitted by sperm donation to recipients. (Voluntary sperm donation through a US Food and Drug Administration–approved tissue bank).

The case

The authors report the case of an asymptomatic 23-year-old man who had no personal knowledge of underlying heart disease and who underwent standard testing that was negative for infectious diseases and repeatedly donated sperm over a 2-year period (1990-1991).

Myocardial Disease


Diagnosis of HCM in the donor

The donor was later known (in 2005) to carry a novel MYH7 mutation that caused HCM, after an offspring was clinically diagnosed with this disease. Of the 24 children known to be offspring of the donor, including 22 who were products of fertilization via sperm donation and 2 conceived by the donor’s wife, a total of 9 genetically affected offspring, 2 to 16 years of age and 6 males, have been identified with HCM (2005-2009).

Phenotype expression

9/22 children (41%) were carriers of the paternal mutation (age 2-16 years; 6 males):
• one has functional limitation with exertional chest pain and fatigue,
• one experienced presyncope and palpitations,
• the other 7 remain asymptomatic.

HCM phenotype in offspring
Two of the living offspring (the above two children with symptoms) have phenotypic evidence of HCM show extreme LV wall thickness involving the ventricular septum of 30mmand 34mm.  One of these children has received a prophylactically implanted cardioverter-defibrillator for prevention of sudden death.
Another genetically affected offspring, died at 2.5 years of age of obstructive HCM (ventricular septal thickness, 22 mm) and progressive heart failure while awaiting transplant.
Six of the 9 genetically affected children do not currently show LV hypertrophy as assessed by 2-dimensional echocardiography at ages 7, 7, 11, 15, 15, and 16 years (mean age, 12 years), although other findings were consistent with phenotypic expression, including mild systolic motion of the mitral valve in one (IV-6) and an abnormal electrocardiogram in the other (IV-3).

Paternal HCM phenotype
The father (III-3) showed segmental LV hypertrophy (thickness, 18 mm) of the posterior (inferior) LV. The electrocardiogram showed T-wave inversion (most prominent in V4-V6), and left atrial enlargement.
CMR showed extensive delayed enhancement consistent with myocardial fibrosis that was largely confined to the hypertrophied region of LV.
Non-mutated offspring
Hypertrophy was absent by echocardiography in each of the 9 offspring with negative genetic testing.

Conclusions

This case underscores the potential risk for transmission of inherited cardiovascular diseases through voluntary sperm donation, a problem largely unappreciated by the medical community and agencies regulating tissue donation. Recommendations include improved screening guidelines for donors to exclude cardiovascular diseases such as HCM and consideration for 12-lead electrocardiograms.


CONSIDERATIONS

A) Transmission of a genetic disease by sperm donation
 

This case fist documents that a genetically determined cardiac disease can be transmitted via sperm donation. A case of Fragile X has also been reported (2). A symptomless donor can be unaware of his disease at the time of donation, especially if cardiological investigations have not been performed. ECG and ECHO are non-obligate tests for apparently healthy donors; a simple ECG control could be sufficient for suspecting HCM, as suggested by the authors. In the setting of cardiovascular diseases, the risk of transmission of an autosomal dominant disease with late penetrance or symptomless exists and is proportional to the prevalence of the disease itself. HCM is the most prevalent autosomal dominant cardiovascular disease in the general population. Other autosomal dominant cardiomyopathies with age-dependant phenotype expression are less prevalent (DCM 1:2500, ARVC 1: 5000) and frequently the family history documents cardiovascular events or affected family members.

B) Hypertrophic cardiomyopathy (HCM)

  • The HCM is a high-prevalence disease (1.500), familial in more than 70% of the cases, and transmitted as autosomal dominant disease. This is a prevalence datum confirmed in more studies in the young- mid-age population.
  • HCM may be asymptomatic or clinically non-manifested, especially considering the age-dependant phenotypes and the possibility of low penetrant mutations.
  • The clinical impact of HCM may vary in different countries and races, with minor negative affects in case of HCM associated with mutation, for example, of the MYBPC3 gene.
  • The risk of transmission by sperm donation exists.

C) Medically assisted procreation and sperm donation

  • The rate of medically assisted procreation and sperm donation to achieve pregnancy, either in the absence of a male partner or in the presence of fertility problems is increasing. Data from media indicate a number of anonymous donor inseminated births per year of 30,000. An unpublished survey conducted by the AATB suggests that a more likely rate would be 4,000 to 5,000 donor-inseminated births per year. By extrapolating this annual figure, the total number of anonymous donor inseminated births is estimated to be less than 130,000 over the last 30 years.  Considering the prevalence of HCM along with the possibility of repeated donations for years, the minimal number of expected HCM is 260 over the last 30 years. One may say that HCM is a “benignant” genetic disease as compared with more severe genetic diseases; however, at least 10% of patients develop malignant complications.

 
CONSIDERATIONS

A) Transmission of a genetic disease by sperm donation

This case fist documents that a genetically determined cardiac disease can be transmitted via sperm donation. A case of Fragile X has also been reported (2). A symptomless donor can be unaware of his disease at the time of donation, especially if cardiological investigations have not been performed. ECG and ECHO are non-obligate tests for apparently healthy donors; a simple ECG control could be sufficient for suspecting HCM, as suggested by the authors. In the setting of cardiovascular diseases, the risk of transmission of an autosomal dominant disease with late penetrance or symptomless exists and is proportional to the prevalence of the disease itself. HCM is the most prevalent autosomal dominant cardiovascular disease in the general population. Other autosomal dominant cardiomyopathies with age-dependant phenotype expression are less prevalent (DCM 1:2500, ARVC 1: 5000) and frequently the family history documents cardiovascular events or affected family members.

B) Hypertrophic cardiomyopathy (HCM)

  • The HCM is a high-prevalence disease (1.500), familial in more than 70% of the cases, and transmitted as autosomal dominant disease. This is a prevalence datum confirmed in more studies in the young- mid-age population.
  • HCM may be asymptomatic or clinically non-manifested, especially considering the age-dependant phenotypes and the possibility of low penetrant mutations.
  • The clinical impact of HCM may vary in different countries and races, with minor negative affects in case of HCM associated with mutation, for example, of the MYBPC3 gene.
  • The risk of transmission by sperm donation exists.

C) Medically assisted procreation and sperm donation

  • The rate of medically assisted procreation and sperm donation to achieve pregnancy, either in the absence of a male partner or in the presence of fertility problems is increasing. Data from media indicate a number of anonymous donor inseminated births per year of 30,000. An unpublished survey conducted by the AATB suggests that a more likely rate would be 4,000 to 5,000 donor-inseminated births per year. By extrapolating this annual figure, the total number of anonymous donor inseminated births is estimated to be less than 130,000 over the last 30 years.  Considering the prevalence of HCM along with the possibility of repeated donations for years, the minimal number of expected HCM is 260 over the last 30 years. One may say that HCM is a “benignant” genetic disease as compared with more severe genetic diseases; however, at least 10% of patients develop malignant complications.

D) Sperm donation (3)

  • Sperm donation is the practice by which a man donates his semen to be used specifically to produce a baby. Donation is usually done in sperm banks. Donors may be either anonymous (most are anonymous) or non-anonymous. The national law may restrict the number of children each donor may father (up to 25). 
  • Potential sperm donors are usually young. The anonymity is controversial and differently regulated in different countries (the identity disclosure is required in some countries but not in others). The consequence of identity disclosure is the shortage of donors, since most donors do not want to be known.
  • A limited donor information released to the woman/couple at most includes height, weight, eye, skin and hair colour. Additional information may be eventually given. Usually, sperm donors are protected by law from being responsible for children produced from their donations, and have no rights over the children generated by their sperm.
  • Several countries only allow non-anonymous sperm donation. The child may, when grown up, get contact information from the sperm bank about his/her biological father (including health status and heritable diseases, if known).
  • Non-institutional donations include "private" donor by advertising (web sites seek to link private donors and donees). Private donations are usually free - avoiding the costs of a medicalised insemination – and, theoretically, the chances of pregnancy may be higher when fresh rather than frozen semen is used. Against this are the usually higher risks of disease transmission and the risk of a legal dispute regarding access or maintenance. In some countries written agreements between donors and donees in a similar way to institutional donations are recognised.
  • The screening of age-dependant heritable diseases, in particular heritable cardiovascular diseases, is impossible. Most sperm banks perform underwent standard testing for infectious diseases, karyotype and test for common genetic diseases such as the recessive cystic fibrosis in the general population (prevalence of healthy carriers 1:30), and genetic conditions common to certain ethnic groups (e.g., sickle cell trait for African Americans).

E) Donor suitability (Sperm banks)

The evaluation of potential donors mostly concentrates on infectious diseases.  In the present case (1), the father was screened by a comprehensive personal and family history, physical examination, and by laboratory testing for infectious and transmittable diseases: 1HIV and HIV2, HTLV1 and HTLV2, syphilis, HCMV, HBV and HCV, gonorrhoea and Chlamydia, as well as Tay-Sachs disease.

Physical examination and family history

The personal and family history was carefully evaluated and the father underwent physical examination. Obviously the family history was negative and there were no apparent reasons for family screening. Obviously physical examination, likely including auscultation, was negative. Most sarcomeric HCM do not show extracardiac traits and therefore it is unlikely that physical evaluation may contribute to suspect a HCM.

By instance, the parents of the donor were not investigated after the positive genetic test (non available).

Overall, based on existing rules, the paternal disease had low probability of being recognised before accepting the donor.

F) The phenotype of affected children seems to be more severe than that of the biological father who was diagnosed after the detection of HCM in one of the 2 offspring conceived by the donor’s wife. The reasons are not clear/known.

G) Ethical considerations

A genetic disease can be transmitted unwittingly to offspring born by medically assisted procedures with sperm donation. The risk is unpredictable. The present case is likely to appear as a unique case, but the number of medically assisted procedures by sperm donation the absence of a male partner or in the presence of fertility problems is increasing. Another potential, remote and unpredictable risk is the mating of half-siblings. This may depend on the geographic utilisation of the donated sperm, as well as the number of children each donor may father; if the number is high (for example 25), the sperm bank serves local requirements, the genetic disease is highly prevalent in the general population and can be clinically silent, the risk remains low but possible. The HCM case is just an example that pertains the WG field of interest. However, the same risk applies to any other genetic diseases without manifest phenotype at the time of donation. Laws that govern sperm donation should be known by geneticists working in the setting of cardiomyopathies and should probably be matter of unified revision in EU countries.

Conclusion:

Question:
Should interview about medically assisted procreation and sperm donation be included in genetic counselling for probands with apparently sporadic (de novo) HCM?

References


Implications of Hypertrophic Cardiomyopathy Transmitted by Sperm Donation. Maron BJ, Lesser JR, Schiller NB, Harris KM, Brown C, Rehm HL. JAMA. 2009;302:1681-4. Erratum in: JAMA. 2009 Nov 11;302:1972

Wirojanan J, Angkustsiri K, Tassone F, Gane LW, Hagerman RJ. A girl with fragile X premutation from sperm donation. Am J Med Genet A. 2008;146:888-892.

Practice Committee of American Society for Reproductive Medicine; Practice Committee of Society for Assisted Reproductive Technology. 2008 Guidelines for gamete and embryo donation: a Practice Committee report. Fertil Steril. 2008;90(5)(5 suppl): S30-S44 

Notes to editor


Presented by  Eloisa Arbustini, Alessandra Serio, Michele Pasotti, Fabiana I Gambarin, Luigi Tavazzi*

Centre for Inherited cardiovascular Diseases, IRCCS Foundation Policlinico San Matteo, Pavia; *GVM Care and Research, Cotignola (Ravenna), Italy.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.