Genetic Testing and Counselling for Nager Syndrome

Introduction

Genetic counselling and testing are essential in assessing the risk and understanding the underlying causes of a genetic condition like Nager syndrome.

The molecular diagnosis of Nager syndrome was made in 2012. The next-generation sequencing tool identified the cause as an SF3B4 gene mutation.¹ Genetic testing and counselling may direct risk assessment, treatment, and management strategies in people with Nager syndrome or a familial history.

This article guides you through genetic counselling, explains its outcomes, and helps you understand the genetic tests available for accurately diagnosing Nager syndrome.

Nager syndrome: an overview

Nager syndrome is a rare developmental disorder characterised by mild to severe bone abnormalities in the head, face, and limbs.^2,3

Though the specific symptoms may vary, the similarity in facial features with other congenital conditions, including Treacher Collins syndrome (TCS), could lead to misdiagnosis.

Is Nager syndrome prevalent?

Nager syndrome is rare and is observed in 3 per 1,000,000 individuals.² The probability of the condition is slightly higher in a person assigned female at birth (AFAB) than in a person assigned male at birth (AMAB).²

While medical literature has reported more than 100 cases of Nager syndrome, many cases could have gone undiagnosed or misdiagnosed.

Why is Nager syndrome a genetic condition?

In 2012, the cause of Nager syndrome was attributed to the SF3B4 gene.¹ The SF3B4 gene instructs the making of the SAP49 protein, which is required for normal embryogenesis, growth, and skeletal development.^1,2 

A mutation in the SF3B4 gene disrupts this process, thereby affecting the development of bones. Variations in the SF3B4 gene mutations cause differences in the symptoms.² 

Is Nager syndrome inherited?

Nager syndrome can be inherited from parents or result from spontaneous mutations in the egg or sperm during fertilisation. 

You should know that an individual has two copies of genes, including the SF3B4 gene, one from each parent. Nager syndrome can be inherited from the parents in two ways:²

Autosomal dominant inheritance

Mutation in a single copy of the SF3B4 gene is sufficient to cause Nager syndrome. An individual with Nager syndrome and a single copy of the mutated SF3B4 gene has a 50% chance of passing it on to their child.

Autosomal recessive inheritance

The individual with Nager syndrome has mutations in both the SF3B4 gene copies, one mutated gene from each carrier parent (unaffected).

Genetic counselling for Nager syndrome: what to expect

What is genetic counselling?

Genetic counselling is a series of sessions that aim at:^4,5

• Identifying families at risk of a genetic condition like Nager syndrome by gathering personal and family health histories
• Assessing the probability of occurrence of the genetic condition
• Educating the family about the genetic condition
• Providing information on genetic testing and procedures
• Empowering autonomy and families in decision-making
• Diagnosing a genetic condition and its predisposition
• Discussing follow-up procedures, management or treatment strategies
• Addressing the family’s psychological issues (e.g., anxiety, blame, grief, guilt, etc)

Who should consider genetic counselling?

Genetic counsellors work in a multidisciplinary team that could include paediatricians, oral, hand, and plastic surgeons, pulmonologists, psychologists, other specialists, and staff.^5,6

Genetic counselling is recommended for prospective parents with a family history of Nager syndrome, affected individuals and their families, and upon prenatal diagnosis.⁵ 

Table 1. Scenario for genetic counselling

What are the stages of genetic counselling?

The stages in genetic counselling depend on the session outcome.

Pre-testing sessions

The genetic counsellor during the session(s):⁴

• Determines the reason for seeking genetic counselling
• Records personal/family history of Nager syndrome
• Discusses the risk and pattern of inheriting Nager syndrome
• Educates about the genetic testing options for Nager syndrome and its limitations
• Refers to a specialised laboratory offering genetic testing (if opted)

Genetic testing

The genetic counsellor will interpret the results of the genetic test.

Post-testing sessions

The genetic counsellor during the session(s):⁴

• Discusses the genetic test results and relevant information
• Help the individual/family cope with the test results
• Refers to a psychological counsellor if required
• Provide educational materials like books and pamphlets for information on Nager syndrome
• Informs about support groups for people with rare genetic conditions and their families

Genetic testing for Nager syndrome

What is the need for genetic testing?

Nager syndrome is primarily diagnosed through characteristic physical features. The similar physical characteristics of the syndrome with other congenital conditions could lead to misdiagnosis.^2,3,6

Though bone abnormalities can be detected during prenatal screening through ultrasound scanning, most often, Nager syndrome isn’t detected. To give you an idea, only 10 of the 100 cases of Nager syndrome were detected prenatally.^2,3

Neonatal (after birth) diagnosis of Nager syndrome is important because the infant may require high-quality neonatal intensive care and treatment, including emergency corrective procedures and surgeries.

A planned management of developmental deformities is essential to improve the quality of life.⁶ Hence, genetic testing is crucial in accurately diagnosing Nager syndrome.^2,3,8

What genetic tests are available for Nager syndrome diagnosis?

A mutation in the SF3B4 gene causes the Nager syndrome.¹ The genetic test ascertains variations in the SF3B4 gene. Variations indicate any change from the normal sequence of units (nucleotides) of the gene.

Research has also pointed to people with Nager syndrome who do not have any SF3B4 gene variations.^2,3 Broad-spectrum molecular-genetic investigations are needed to rule out other genetic conditions with similar physical features and accurately diagnose Nager syndrome.^2,3,6

Genetic investigations to detect mutations causing Nager syndrome

Broad molecular-genetic investigations involve scanning not just the selected genes (SF3B4) but other genes too. 

Broad genetic investigations can screen specific genes linked to a disease group (gene panel diagnostics), coding areas of the genome (whole exome sequencing, WES), or the entire genome (whole genome sequencing, WGS).

Investigations like this allow the detection of a wider range of genetic mutations, including the SF3B4 gene mutation (if any), responsible for the features of the syndrome.

Chromosomal microarrays can detect extra or missing pieces in chromosomes that can cause physical deformities.

A prenatal microarray genetic test was used to diagnose the structural abnormalities found during the prenatal ultrasound. It was found that a part of the SF3B4 gene had been deleted. Thereby, diagnosing the foetus with Nager syndrome and allowing genetic counselling of the family.^9,10

CT scans and X-ray methods supplement genetic tests in diagnosing rare conditions like Nager syndrome.

Table 2. Genetic tests to diagnose Nager syndrome (Genetic Testing Registry, NIH)

Learn how molecular-genetic investigations like whole genome sequencing (WGS) and whole exome sequencing (WES) prove to be valuable tools in the diagnosis of Nager syndrome.

FAQs

Where can I get my genetic testing done?

If you think you or a family member has a genetic condition, consult a healthcare professional. If you have been advised to do genetic testing by your doctor, it is more likely that you have also been referred to a genetic counsellor. 

The genetic counsellor would guide you through the genetic testing process, refer you to a specialised laboratory for your genetic test, and help you understand and endure the results.

You should know that only a licensed healthcare professional may order a genetic test for a medical condition.

Here are some of the directories of registered genetic counsellors by region: United Kingdom, United States of America, Canada, Australia, and New Zealand.

How long will it take to get the genetic test results?

Your genetic counsellor will inform you when to expect your test results during the pre-testing session. The duration to generate the test report depends on the referred test. It could take anywhere between 2 and 6 weeks to get your genetic test results. 

Is there any genetic therapy for Nager syndrome?

There is no genetic therapy available for Nager syndrome. As of today, the symptoms of the genetic condition are managed through surgical interventions and physiotherapy.

Summary

• Mutations in the SF3B4 gene are the molecular diagnosis for Nager syndrome
• Genetic counselling helps educate, diagnose, and guide individuals with familial history, symptomatic infants, asymptomatic children and families of people with Nager syndrome
• With genetic tests and management strategies, genetic counsellors educate and guide individuals and families affected with Nager syndrome during pre- and post-testing sessions
• Genetic tests for Nager syndrome involve broad genetic investigations such as gene panel diagnostics, whole exome sequencing, or genome sequencing
• Analysis of variations in the SF3B4 gene with next-generation sequencing is the specific diagnostic test for Nager syndrome
• Accurate diagnosis is important for timely and proper medical intervention to improve the quality of life for individuals with Nager syndrome