Exome sequencing is not an answer to all questions, importance of clinical examination still exists!

A couple enters in my OPD with eyes full of tears and hopelessness with a document file with loads of papers. They had lost their baby at 6 days of his life due to neonatal hypotonia and difficulty to feed.

They had had an uneventful pregnancy with a spontaneous conception, normal NT scan, low risk dual marker test and non-invasive prenatal screening for aneuploidy and normal anomaly scan. Mild polyhydramnios was noted at 30 weeks of gestation. A male baby weighing 3 Kg was delivered at term by elective cesarian section, cried after birth but was extremely hypotonic with poor respiratory effort. He was immediately transferred to NICU but lost his life at day 6. Metabolic investigations were normal. Exome sequencing and microarray were sent as part of a genetic workup. Exome sequencing had detected a couple of variants which were classified as variants of uncertain significance and hence genetic diagnosis was inconclusive. The couple was extremely worried for their future pregnancy and was looking for answers.

While talking to them I noticed a little dull expression on lady’s face which I initially disregarded and thought it might be due to recent loss of her baby. However, considering a prominent history of neonatal hypotonia, I checked with a simple clinical sign for grip myotonia by handshaking with her. I could notice the mild evidence for myotonia [which was later confirmed by electromyography]. During extended examination I found out the presence of proximal and distal muscle weakness in lower limbs. She had also noticed loss of hair for past 2-3 years. These pieces in history and clinical examination were sufficient for me to make a presumptive diagnosis of Myotonic Dystrophy. Later, eye examination revealed bilateral posterior subcapsular cataract which was also part of spectrum. Echocardiography was normal.

Myotonic dystrophy type I is a specific class of genetic disorder caused by a “CTG” repeat expansion in DMPK gene and may affect almost every organ system in the body. Predominantly muscles, heart, eyes, endocrine systems are affected. Symptoms usually appears in second or third decade and slowly progressive. Based on the size of the “CTG” expansion the clinical features can be classified into mild, classical and severe neonatal.

This group of disorders are not diagnosable in routine genetic tests like karyotype, microarray or exome sequencing and a separate specific test [Triple Prime PCR] is required. Another unique characteristic of this condition is “anticipation”, which means when a mutation copy of a gene is transferred to future generation, expansion size may increase and becomes more severe with successive generation. DMPK gene repeat expansions particularly increases in size when transferred through oocyte [maternal inheritance].

Triple Prime PCR testing result in her sample showed the CTG repeat expansion in DMPK gene confirming the diagnosis of myotonic dystrophy. It is an autosomal dominant disorder with 50% chance of recurrence in each successive pregnancy. However now with an established genetic diagnosis, we can offer a definitive prenatal diagnosis with the hope of healthy pregnancy outcomes.

The case highlights the following points

1. Clinical acumen is still required even in advanced genomic diagnostic era.
2. Selection of right genetic test is extremely important which depends upon detailed history and relevant clinical examination.
3. Exome sequencing is not a one time solution to all genetic problem.s Interpretation of genome wide testing is an intricate art which should be best done be health care professionals trained in it.
4. Genetic testing may remain inconclusive in many families