Parental Carrier Screening for Autosomal Recessive and X- Linked Disorders

Preconception screening refers to the evaluation of par ents for the risk for genetic disorders in their future children before the pregnancy. This is the optimal time to offer and perform carrier screening, but it is infrequently done preconceptionally. Therefore risks for autosomal recessive and X- linked single- gene disorders and carrier screening should also be addressed in prenatal counseling. The approach to carrier screening has evolved over time. It initially relied on targeted screening for a few diseases, based on individual risk factors assessed through family history, such as a prior affected child, the presence of consanguinity, and information on the ancestry of the prospective parents. With the currently available high- throughput laboratory methods, cost- effective rapid sequencing of many genes is now available and allows for a more equitable approach to carrier screening with larger panels of genes. The ACMG now recommends that carrier screening is offered to all pre conception or pregnant patients and their reproductive partners in an ancestry and population neutral fashion. They recommend using a panel with genes for 97 autosomal recessive and 16 X- linked conditions with a carrier frequency at or greater than 1/ 200 to be offered to all pregnant patients while reserving larger panels with additional disease genes for patients with possible con sanguinity or when warranted based on family or medical history.

Couples who are carriers for pathogenic or likely pathogenic variants that increase the risk for inherited recessive or X- linked disease in their current or future pregnancy should be offered appropriate counseling about reproductive options and residual risk. Preconceptionally, they can consider preimplantation genetic testing for monogenic disorders (PGT- M), use of donor eggs or sperm, adoption, or the option to forgo having children. They can also choose to conceive and have CVS or amniocentesis during the pregnancy or testing of the infant at the time of birth.

Preimplantation Genetic Testing

 PGT, formerly referred to as preimplantation genetic diagnosis (PGD), is performed on in vitro fertilized embryos prior to embryo transfer (Fig. 1). PGT offers couples at significant risk for a specific genetic disorder or aneuploidy in their offspring an option to manage reproductive risks that avoid pregnancy termination. In the most commonly used approach, blastocyst biopsy (see Fig. 1), women have to undergo IVF. They first undergo ovarian stimulation and retrieval of ~10 or fewer oocytes in the stimulated cycle. The oocytes are then fertilized in vitro and cultured for 5 to 6 days until the blastocyst stage. At that time, 5 to 10 cells are retrieved from the trophectoderm, which develops into the future placenta, without disrupting the inner cell mass, which will develop into the fetus. PGT was initially done by blastomere biopsy on eight- cell– stage embryos, but trophectoderm biopsy on blastocysts, which provides more cellular material and apparently greater accuracy, is now preferred. Usually, biopsied embryos are frozen while the molecular diagnosis proceeds. One of the embryos that are found not to carry the genetic abnormality in question can then be transferred and allowed to implant in a future cycle, as is routinely done after IVF. Affected embryos are dis carded. Data currently available suggest that there are no detrimental effects to embryos that have undergone biopsy.

Fig1. Preimplantation genetic diagnosis. After ovarian stimulation, oocytes are retrieved and fertilized in vitro. The fertilized embryos are incubated for 5 to 6 days, to the blastocyst stage, and about 5 to 10 cells are removed from the trophectoderm, which will develop into the placenta. These cells will be used for genetic testing for chromosomal abnormalities or single- gene disorders. In this example, the embryo (labeled X) will not be transferred. Only embryos that are unaffected will be transferred into the patient’s uterus to establish a pregnancy.

There are three types of PGT: PGT monogenic (M) evaluates for single- gene disorders, PGT aneuploidy (A) evaluates for whole chromosome abnormalities, and PGT structural rearrangements (SR) is used to detect structural chromosomal abnormalities such as translocations. PGT- M is utilized to detect known pathogenic variants in specific genes that were previously found in a family member with a genetic disorder or through parental carrier screening. It involves PCR amplification followed by a method to detect the variant. Because of the small amount of starting material, analysis of linked polymorphic markers is often included to improve accuracy.

Initially, FISH and later microarray analysis were used to detect chromosome abnormalities, but more recently laboratories have switched primarily to next generation sequencing methods to detect CNVs for PGT- A and unbalanced translocations. PGT- A is now offered to women undergoing IVF to increase the live birth rate by only selecting euploid embryos for transfer. The American Society of Reproductive Medicine recommends offering PGT- A to all infertile women, but research is ongoing to fully establish the clinical utility of PGT- A.

Despite technologic improvements in recent years, there are limitations to PGT. These include mosaicism and challenges with detecting de novo mutations, micro deletions, and duplications. Because with PGT diagnoses are made on small numbers of cells, women who have PGT- M and PGT- SR should be offered confirmatory CVS or amniocentesis during ensuing pregnancies. Because of the small risk (~2– 3%) for false- positive and false- negative results with PGT- A, it is considered good practice to offer prenatal aneuploidy screening for pregnancies conceived by IVF with PGT- A. Although PGT was developed to avoid the ethical, religious, and psychological difficulties with pregnancy terminations, ethical dilemmas remain related to the disposition of affected embryos and remaining frozen healthy embryos after parents have completed their family.

اخر الاخبار

اخبار العتبة العباسية المقدسة

30 قارئًا يشاركون بـ18 ختمة قرآنية رمضانية في محافظة الديوانية

الحوزة العلمية تقيم مجلس فاتحة الشهيد السيد علي الخامنئي (رضوان الله عليه)

تأهّل 5 مشاركين للمرحلة النهائية من جائزة العميد الدولية لتلاوة القرآن الكريم

محفل نهج البلاغة الأسبوعي في ذي قار يشهد تقديم المحاضرة الخامسة

المزيد

الآخبار الصحية

مركب طبيعي في القهوة يحمينا من التهابات اللثة

داء السكري لا يرفع السكر فقط.. بل يزيد خطر الإصابة بأمراض القلب!

اكتشاف سبب غير متوقع لضعف الذاكرة والتركيز

نصائح علمية لتقوية دماغك وتقليل التدهور العقلي

المزيد

الآخبار التكنلوجية

باحثون يرصدون أثر تغيّر المناخ في دم البشر

الجميع يحلم.. لماذا يتذكر البعض أحلامهم بينما ينسى آخرون؟

حرق الأمونيا.. كيف يساعد محطات الكهرباء في اليابان على إزالة الكربون؟

الشمس تقذف نتوءا عملاقا باتجاه قطبها الشمالي

المزيد

مواضيع ذات صلة

X-Linked Inheritance

Problems in Prenatal Chromosome Analysis and Gene Sequencing

Introduction to Cytogenetics and Genome Analysis

Methods to Detect Fetal Chromosomal Abnormalities

The Origin and Frequency of Different Types of Mutation

Noninvasive Prenatal Screening by Analysis of Cell- Free Fetal DNA

Screening for Down Syndrome and Other Aneuploidies

Screening for Neural Tube Defects

Genetic Alterations Associated with Acromegaly

The Profession of Genetic Counseling

Applying Genomics to Individualize Cancer Therapy

The Role of Epigenetics in Cancer