By Rossana Sánchez, M.D.

Medical Genetics is a vast and rapidly advancing field. With an estimated 20,000 to 25,000 genes in the human genome, mutations in these genes give rise to many disorders. The scope of practice of a geneticist is necessarily broad, encompassing inpatient and outpatient consultations for inherited conditions and congenital malformations, for genetic counseling and risk assessment, for treatment of genetic diseases and prevention of complications, as well as for ordering genetic and genomic testing¹. The focus of genetics as a science is not solely on the patient, either, but also the patient’s family.

Preconception and Prenatal

The need for a medical geneticist may arise very early, sometimes even prenatally. As the science advances, mothers-to-be are offered special screening options for genetic conditions, such as the first and second trimester screen and the newer noninvasive prenatal testing (NIPT)². These tests are designed to screen for aneuploidies (abnormal chromosomal numbers) of select chromosomes in the fetus via maternal blood. Common disorders caused by aneuploidies are trisomy 21 or Down syndrome, trisomy 13 and trisomy 18. It is common to offer this testing to mothers who are over 35 years of age, which is called “advanced maternal age.” The reason this age was originally chosen as an ideal screening time is because the risk of having a baby with Down syndrome was comparable to the risk of having a miscarriage as a result of an invasive procedure like amniocentesis to confirm this same diagnosis.

Usually, a certified genetic counselor explains all testing to parents and discusses age-related chromosomal problems when presenting results. If any of the screening tests are positive, then the mother should be offered confirmatory testing via amniocentesis. If an aneuploidy is diagnosed, then she and her partner will receive further genetic counseling so they have adequate information about the disease and understand their options. Confirmatory testing may also be offered if there are any fetal abnormalities seen in the ultrasound, including abnormal nuchal (posterior neck) translucency. Prenatal testing via amniocentesis or chorionic villus sampling (CVS) can also be offered for other genetic conditions that are present in the family if the mutations for a disease are known. Antenatal testing may also be offered to couples who have a family history of a disorder and wish to know if they are carriers and to couples with multiple (more than two) miscarriages or multiple stillbirths.

Some couples may also need preconception genetic testing. This is known as carrier testing or a carrier screen³. Most people are carriers of genetic disorders that are recessive, and females can be carriers of X-linked disorders. Carriers do not usually have any signs or symptoms; however, if both partners in a couple are carriers for the same recessive condition, then the chances of a child being affected are 25 percent for each pregnancy. If a mother is a carrier of an X-linked disorder, then males have a 50 percent chance of being affected, and females have a 50 percent chance of being carriers.

Ethnicity may also affect the chances of being carriers of certain disorders. For example, cystic fibrosis is well known to be more common in Caucasians, Tay-Sachs is more common in the Jewish population, and sickle cell disease is more common in African Americans. This is why initiatives like the Jewish Screen, or JScreen, started. It initially screened for common mutations in genes that caused diseases in this population, but it has now expanded to include more genes and full gene sequencing to detect mutations in other populations, becoming a pan-ethnic carrier screen.

Couples who are carriers of a known genetic disorder and whose mutations are known also have a chance to deliver healthy children via pre-implantation genetic diagnosis, or PGD⁴. This is a procedure used to screen embryos made via in vitro fertilization for genetic conditions, and then only unaffected embryos are implanted in the mother.

Neonatal

After birth, if any malformation is noted in a baby, a geneticist should be consulted. Common birth defects include cleft lip and palate or a congenital heart defect, which may be isolated and nonsyndromic, meaning it is not related to other findings. These defects may also be seen as part of other disorders. A geneticist might recognize patterns that lead to a specific diagnosis or suggest a need for testing. It is common to order a chromosomal microarray test when there are multiple congenital anomalies that are not explained by maternal exposures or deformations in utero⁵. This test helps uncover missing or extra copies of genetic material, known as deletions and duplications, respectively, which may explain the myriad of symptoms a baby has. If a diagnosis is confirmed, then there will be counseling with the family to discuss the diagnosis, possible complications and risks of recurrence.

In the neonatal period also comes the challenge of positive newborn screens. In the state of Georgia, we currently screen for more than 40 conditions. The false-positive rate tends to be high, so we must follow many children until confirmatory testing is complete. Some of the babies who are true positives appear clinically ill, even before the screen is back. Thus, inborn errors of metabolism should be considered in cases of suspected sepsis, seizures, lethargy, hyperammonemia or an anion gap acidosis, amongst other findings. In all these cases, a biochemical geneticist and metabolic nutritionist should be contacted and brought into the team treating the patient. If a metabolic condition is diagnosed, then the patient will be followed by geneticists throughout his or her lifetime.

Infancy and Childhood

During infancy and childhood, common reasons to refer to a geneticist include developmental delay or developmental regression and autism or pervasive developmental disorder (PDD). Developmental regression tends to be a more ominous sign but can be seen in many different disorders, including some inborn errors of metabolism like Tay-Sachs, neurological conditions like neuronal ceroid lipofuscinosis or Rett syndrome^6,7,8. Developmental delay may be fairly nonspecific and ubiquitous in many disorders. A thorough history, physical exam and pedigree can help focus the diagnosis and target the testing strategy. Moreover, autism and PDD may have an underlying genetic cause, and genetic testing is warranted in the initial stages of evaluation⁸.

Another concern at this age is muscle weakness or hypotonia; again, this may be due to a number of different disorders, and it is important to rule out spinal muscular atrophy, Prader-Willi syndrome, and muscular dystrophy, amongst other disorders⁹. A simple CPK screen can help differentiate a muscular dystrophy from other disorders, but it is not always abnormal.

Abnormal growth patterns may also indicate a genetic disorder. Such patterns include both short and tall stature or failure to thrive¹⁰. Many skeletal dysplasias present with disproportionate short stature, so measuring a patient’s limbs and obtaining the height of other family members are recommended. Overgrowth syndromes, such as Sotos syndrome, are also seen and usually present with increased weight, height and head circumference that may be present from birth¹¹.

Evidence of congenital or early-onset blindness or deafness warrants a genetics consult. It is important to rule out syndromic causes for these and assess for family history of potentially inherited conditions. One common autosomal dominant trait, for instance, is congenital cataracts. When signs and symptoms of an unknown disease follow a Mendelian pattern of inheritance or there is a family history of a known condition, patients should also be referred to genetics.

Adolescence and Adulthood

We customarily see patients during adolescence who have abnormal growth patterns. Patients with tall stature and other findings of common disorders like Marfan syndrome or Klinefelter syndrome should be assessed by a clinical geneticist¹¹. Many of these patients present with other findings, and the work-up may be started by the primary care physician. If, for instance, a diagnosis of Marfan syndrome is considered, then an eye exam and an echocardiogram could be ordered. Another common reason for referral is abnormal sexual maturation. It is important in these cases to rule out disorders of sex development or intersex conditions¹². Chromosomes should be analyzed for both growth abnormalities and sexual maturation anomalies.

In this age group, it is also common to receive referrals for a strong family history of cancer or when the types of cancer are rare. Usually, these patients are seen by a certified counselor in the Cancer Genetic Counseling Clinic who obtains a family history and orders testing for known cancer syndromes¹³. Depending on which genes are found to have mutations, the risks for different cancers increase in different percentages, and follow up with counselors is warranted to explain recurrence risks, practice guidelines and to offer testing to other relatives at risk.

We commonly receive referrals for mutations in the MTHFR gene, which has been linked to mildly elevated homocysteine levels in blood. Hyperhomocysteinemia has been associated with increased risk of developing cardiovascular disease and venous thrombosis¹⁴. That said, a person with the common polymorphisms in the MTHFR gene, even in the homozygous state, but with a normal homocysteine level does not require management or referral to genetics. All women regardless of MTHFR status should take folic acid supplements preconceptionally and during pregnancy to lessen the risk for neural tube defects at the recommended daily allowance of folate (0.4 mg/day) ¹⁵.

Table 1. Indications for Medical Genetics Referral

Abbreviations: AFLP: Acute fatty liver of pregnancy. US: Ultrasound. IUGR: Intrauterine growth restriction. FTT: failure to thrive. PDD: Pervasive developmental delay.

* Table adapted from Reference 16.

References:

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3. Wayne W. Grody et al. ACMG position statement on prenatal/preconception expanded carrier screening. Genetics in Medicine (2013) 15,482–483
4. Harvey J. Stern. Clin. Preimplantation Genetic Diagnosis: Prenatal Testing for Embryos Finally Achieving Its PotentialMed. 2014, 3, 280-309.
5. Jay W. Ellison et al. Clinical Utility of Chromosomal Microarray Analysis. PEDIATRICS (2012) Vol. 130 No.5.
6. M A Cleary, A Green Developmental delay: when to suspect and how to investigate for an inborn error of metabolism. Arch Dis Child 2005;90:1128–1132.
7. Anita Rauch et al. Diagnostic Yield of Various Genetic Approaches in Patients with Unexplained Delay or Mental Retardation. AJMG Part A 140A:2063-2074.
8. Judith H. Miles. Autism spectrum disorders-A genetics review. Gentics in Medicine (2011) Vol 13, No.4.
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12. Ieuan A. Hughes. Disorders of Sex Development: a new definition and classification. Best Practice & Research Clinical Endocrinology & Metabolism Vol. 22, No. 1, pp. 119–134, 2008.
13. Jill E. Stopfer. Genetic counseling and clinical cancer genetic services. Seminars in Surgical Oncology 2000: 18:347 – 357.
14. Hickey et al. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genetics in Medicine (2013)15,2.
15. Clarke R, Bennett DA, Parish S, et al. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. PLoS Med 2012;9:e1001177.
16. Beth A. Pletcher et al. Indications for genetic referral: a guide for healthcare providers. ACMG Practice Guideline. (2007) Vol 9. No.6.