CUHK Medical Centre Genetic Disease Intervention: Suitable Candidates & PGT Process Explained

Opening: Doctor's Decision Logic (Random Selection Mechanism 6)

In the reproductive medicine genetic counselling clinic, when a couple seeks assisted reproductive help due to genetic disease issues, the doctor's decision path usually follows a clear clinical logic: the first step is to clarify the diagnosis and inheritance pattern of the genetic disease, the second step is to assess the recurrence risk and the necessity of intervention, the third step is to determine the applicability of preimplantation genetic testing (PGT) technology, and the fourth step is to formulate an individualised testing plan. In the field of genetic disease intervention, the CUHK Medical Centre, relying on the genetics team and molecular diagnostic platform of the Faculty of Medicine at The Chinese University of Hong Kong, has formed a complete closed loop from genetic counselling to PGT testing. The following, from a clinical perspective, outlines which individuals requiring genetic disease intervention are suitable for this hospital, along with the underlying medical rationale and operational pathways.

1. Who is suitable for genetic disease intervention at CUHK Medical Centre?

The core of the genetic disease intervention service provided by the Assisted Reproduction Centre of CUHK Medical Centre is preimplantation genetic testing (PGT), which includes three types:

• PGT-M (Monogenic Disease Testing) – For monogenic genetic diseases with a clear causative gene, such as thalassaemia, spinal muscular atrophy (SMA), hereditary hearing loss, cystic fibrosis, Huntington's disease, etc.
• PGT-SR (Structural Rearrangement Testing) – For carriers of chromosomal structural abnormalities, such as balanced translocation, Robertsonian translocation, inversion, microdeletion/microduplication, etc.
• PGT-A (Aneuploidy Screening) – For screening chromosomal number abnormalities in embryos, suitable for individuals of advanced maternal age, those with recurrent miscarriage, recurrent implantation failure, etc., also falling under the broad category of genetic disease intervention.

Specific groups suitable for choosing this hospital for genetic disease intervention include:

• One or both partners are carriers of a pathogenic gene for a monogenic genetic disease and wish to have healthy offspring.
• One or both partners are carriers of a balanced chromosomal translocation or Robertsonian translocation, have a high risk of miscarriage, and wish to select embryos with normal structure.
• Those with a family history of genetic disease, but the specific causative gene is not yet identified, requiring carrier screening and genetic counselling first.
• Women aged ≥38 years, or those with a history of miscarriage due to chromosomal aneuploidy, hoping to reduce the risk of another miscarriage through PGT-A.
• Those who have previously given birth to a child with a genetic disease and wish to avoid having another child with the same condition.

2. How do doctors assess the necessity of genetic disease intervention?

In the genetic counselling clinic at CUHK Medical Centre, doctors primarily base their assessment of the need for PGT genetic disease intervention on the following principles:

1. Recurrence risk of the genetic disease

For autosomal dominant diseases, the recurrence risk for offspring of an affected patient is 50%; for autosomal recessive diseases, when both partners are carriers, the risk of the offspring being affected is 25%; for X-linked recessive diseases, daughters of an affected male are carriers, sons are normal, and sons of a female carrier have a 50% risk of being affected. When the recurrence risk is higher than 5%, PGT intervention is usually recommended.

2. Severity of the disease

For genetic diseases that may cause severe intellectual disability, early death, or failure of vital organs (e.g., Tay-Sachs disease, Duchenne muscular dystrophy, severe thalassaemia), the medical necessity for PGT intervention is strong. For diseases with mild symptoms or those that manifest only in adulthood, the doctor will make a comprehensive judgement based on the family's wishes.

3. Feasibility of testing technology

CUHK Medical Centre requires that the causative gene for the genetic disease is identified, the mutation site is known, and the corresponding single-cell amplification and detection technology is available. For diseases where the causative gene is not identified or the inheritance pattern is complex, preliminary tests such as whole exome sequencing of the family must be completed first.

3. Clinical definition of suitable and unsuitable candidates

Suitable Candidates

Unsuitable Candidates

• Sex selection for non-medical reasons only – Hong Kong law prohibits PGT testing for the purpose of sex selection without medical necessity.
• Very low genetic risk and no clear indication – Couples with no family history of genetic disease, no history of recurrent miscarriage, female age <35 years, with no medical reason for PGT screening.
• Unidentified causative gene or inaccessible testing technology – For some rare genetic diseases, the causative gene has not been identified, or the mutation type is unsuitable for existing testing platforms, making it impossible to design an effective PGT protocol.
• Severely diminished ovarian function preventing retrieval of sufficient eggs – PGT requires biopsying cells from the embryo for testing. If very few eggs are retrieved (≤2), there may be no embryos available for testing and transfer.

4. Actual PGT process for genetic disease intervention at CUHK Medical Centre

The complete PGT process is usually divided into the following stages, each with clear timelines and key operations:

The entire process, from the initial genetic counselling to embryo transfer, typically takes 4-6 months. The waiting period for the genetic testing report (4-6 weeks) is the longest step, and patients should plan their time accordingly.

5. Key milestones in the timeline

For patients planning to undergo genetic disease intervention at CUHK Medical Centre, the following time points require special attention:

• Genetic counselling appointment – It is recommended to book the genetic counselling clinic 1-2 months in advance, especially for cases requiring carrier screening and family verification.
• Carrier screening results – Whole exome sequencing reports usually take 3-4 weeks; expedited service can shorten this to 2 weeks but incurs additional costs.
• Probe design & verification – PGT-M protocol design takes 4-8 weeks; complex cases (e.g., de novo mutations, mosaicism) may take longer.
• Ovarian stimulation cycle – Must be scheduled around the menstrual cycle; it is recommended to start only after the genetic protocol design is complete.
• Waiting for test report – Results are available 4-6 weeks after embryo biopsy; embryos must be cryopreserved during this period.

6. Details most easily overlooked during genetic counselling

Based on practitioner observations, the following details are often overlooked by patients during the genetic disease intervention process but have a significant impact on the success of testing:

• Importance of the proband's sample – If there is a previously affected child in the family (proband), their DNA sample is crucial for identifying the pathogenic mutation and designing the testing protocol. Some families face difficulties in designing the PGT-M protocol because they did not preserve the proband's sample or cannot provide detailed medical records.
• Both partners must undergo carrier screening simultaneously – Screening only one partner cannot fully assess the recurrence risk of recessive genetic diseases. The standard protocol at CUHK Medical Centre requires blood samples from both partners to be tested at the same time.
• Karyotype analysis cannot be omitted – Even if both partners have a normal phenotype, approximately 0.5% of the population carries a balanced chromosomal translocation or Robertsonian translocation. Routine karyotype analysis is a prerequisite for PGT-SR.
• Choice of testing platform – Different genetic diseases require different testing platforms. For example, dynamic mutation diseases (e.g., Huntington's disease, Fragile X syndrome) require special amplification techniques, which not all laboratories are equipped to perform.
• Issue of embryo mosaicism – Biopsied cells may not fully represent the genetic status of the entire embryo, posing a risk of missing mosaicism. Doctors usually recommend prenatal verification via amniocentesis for embryos with normal PGT results.

7. Handling special situations

Mitochondrial genetic diseases

Diseases caused by mitochondrial DNA mutations (e.g., Leber's hereditary optic neuropathy, mitochondrial encephalomyopathy) have complex inheritance patterns, making them difficult to completely avoid with conventional PGT-M. The strategy at CUHK Medical Centre for mitochondrial genetic diseases is: first, test the mitochondrial DNA mutation load, and select embryos with a mutation load below the pathogenic threshold. The hospital has established a clinical pathway for PGT for mitochondrial diseases, but feasibility should be confirmed with the genetic counselling team in advance.

Risk of polygenic diseases

For polygenic diseases (e.g., congenital heart disease, neural tube defects, schizophrenia), which involve multiple genes and environmental factors, current PGT technology cannot effectively predict them. CUHK Medical Centre does not recommend PGT intervention for polygenic diseases. Doctors will advise patients to monitor during pregnancy through prenatal ultrasound and serum screening.

De novo mutations

If the genetic disease is a de novo mutation (neither partner carries the pathogenic gene, but the child is affected), the mutation source must first be confirmed through family whole exome sequencing, and then a PGT-M protocol targeting that mutation site can be designed. Due to the lack of a proband sample, protocol design is more difficult and requires a longer time.

8. Frequently asked questions

1. What is the accuracy of PGT testing at CUHK Medical Centre?

The accuracy of PGT testing depends on several factors, including the quality of the biopsied embryo cells, amplification efficiency, and sensitivity of the testing platform. Currently, the accuracy of PGT-A for chromosomal aneuploidy is approximately 95-98%, and the accuracy of PGT-M for monogenic diseases is approximately 95-99%. However, 100% accuracy cannot be guaranteed due to technical limitations such as amplification failure, allele dropout (ADO), and mosaicism. For all embryos with normal PGT results, doctors still recommend amniocentesis in the second trimester for verification.

2. What materials are needed for PGT testing?

• Identification documents for both partners (Mainland Travel Permit/Passport).
• Previous medical records related to the genetic disease (genetic test reports, medical history, family history documents).
• If a proband exists, provide their DNA sample or blood/tissue sample.
• Infectious disease screening reports for both partners from the last 3 months (Hepatitis B, Hepatitis C, Syphilis, HIV).

3. Does PGT testing harm the embryo?

Embryo biopsy involves removing 5-10 cells from the trophectoderm of the blastocyst (which will develop into the placenta) and does not damage the inner cell mass (which will develop into the foetus). Multiple studies have shown that the success rate of embryo transfer after PGT biopsy is not significantly different from that of non-biopsied embryos. However, biopsied embryos need to be cryopreserved and thawed for transfer after the test results are available.

4. What if all embryos are abnormal?

This is the situation requiring the most psychological preparation in PGT testing. For carriers of genetic diseases, especially translocation carriers, the proportion of normal embryos may be only 20-40%. If all embryos are abnormal, it means there are no transferable embryos in that cycle. Doctors will advise considering another ovarian stimulation cycle, using donor gametes, or alternative options such as prenatal diagnosis combined with selective reduction.

Related Topics CUHK Medical Centre genetic counselling process · Factors affecting PGT testing costs in Hong Kong · Time required for carrier screening for genetic diseases · How long does embryo genetic testing take · PGT-SR protocol design for chromosomal translocations · PGT-M probe preparation for monogenic diseases