The possible implications of advances in genetic testing technologies for Genetic Counsellors working with families of children with developmental disorders

Introduction

Projects such as the Deciphering Developmental Disorders (DDD) study, and the 100,000 Genomes project, have used whole exome or genome sequencing to pinpoint disease causing mutations, increasing the chance of making a diagnosis in individuals with developmental disorders. This type of technology is a realistic possibility for clinical NHS care in the UK within the not-too-distant future (Hazelton & Petchey, 2015). In this paper, I explore the implications this could have for Genetic Counsellors supporting families of children with developmental disorders as they go through the diagnostic journey.

Developmental disorders may manifest in any area of development (e.g. growth, congenital malformations, seizures) but the most common phenotype is developmental delay (DD) or intellectual disability (ID) (Deciphering Developmental Disorders Study, 2015) which are common referral indicators to Clinical Genetic Services. ID is defined by the World Health Organisation as having an Intelligence Quotient (IQ) below 70 and can be classified as mild, moderate, severe or profound (World Health Organisation, 2015). It is estimated to affect approximately 1–3% of the population (Shaffer, 2005). The term ‘Intellectual Disability’ is generally only used when a person is of an age when an IQ test is valid and reliable, which is typically from 5 years old (Shavell et al., 2003). Prior to this the term DD is used. DD may present itself in any of the following areas: gross/fine motor, speech/language, cognition, social/personal, and activities of daily living (Shavell et al., 2003). If a child has delay in two or more of these areas they are said to have Global Developmental Delay (GDD). The estimated prevalence of GDD is about the same as ID at approximately 1–3%. It is estimated that 5–10% of all children have some sort of DD, therefore DD or even GDD may not necessarily lead to ID, but children with ID often had DD in their early years (Shavell et al., 2003).

Parental responses to having a child with a developmental disorder

It is natural for parents to hope for a healthy child. The point when a developmental disorder may become apparent can range from a prenatal scan, to birth, to later on as the child grows. This can be a sudden or a gradual realisation (Heiman, 2002; Lewis et al., 2010). Initial reactions to this realisation are likely to be negative such as disbelief, anger, denial, and grief (Graungaard & Skov, 2007; Heiman, 2002; Kearney & Griffin, 2001; Lewis et al., 2010). From this initial reaction, parents must go through a process of adaptation of “replacing the hopes and expectations…with the realities of their child’s actual prognosis” (pg 186, Barnett et al., 2003). This process has been likened to that of a ‘journey’ that at times is like a ‘rollercoaster’ full of highs and lows (Lewis et al., 2010).

For parents to adjust appropriately to the reality of having a disabled child, they must adopt a number of coping strategies. These may be practically or emotionally-directed (Graungaard & Skov, 2007; Lewis et al., 2010; Rosenthal et al., 2001). Practical coping strategies may be information gathering e.g. about disease prognosis, treatments or research opportunities. Emotional coping strategies may be talking with friends and family or accessing support services. Some of the studies cited earlier went on to explore parental feelings after they have gone through this period of adaptation. They found that many parents have positive and optimistic feelings about their child’s future (Heiman, 2002; Kearney & Griffin, 2001; Lewis et al., 2010).

Although the majority of parents appear to adapt well to their new reality, some parents and families are less successful. Traits of less successful adaptation may be: unrealistic appreciation of their child’s weaknesses and limitations; continued feelings of self-pity and guilt; searching for a ‘magical solution’; and feelings of rejection or over-protection of their child, sometimes at the expense of other family members (Kandel & Merrick, 2007). This inability to cope and adapt can have a negative effect on mental health (e.g. stress, depression), relationships and functioning (Barnett et al., 2003).

A developmental disorder can leave families with many questions, some of which can only be answered by obtaining an accurate diagnosis. In this way, searching for a diagnosis can form part of the process of coping and adaptation. Below is a list of reasons given for seeking a diagnosis that has been amalgamated from a range of studies. Most of these studies are of parents of children with developmental disorders, but one includes responses from adults with genetic disorders (Hazelton & Petchey, 2015). A range of methods were used including semi-structured interviews (Lewis et al., 2010; Makela et al., 2009; Rosenthal et al., 2001) and surveys (Hazelton & Petchey, 2015; Limb et al., 2010; Madeo et al., 2012).

Diagnostic tools employed for individuals with developmental disorders

Traditionally, those fulfilling the clinical features of a recognised syndrome may be diagnosed on clinical examination alone. As technology has advanced, other diagnostic tools have become available, such as metabolic studies, EEG, CT/MRI imaging, cytogenetic studies (e.g. karyotype, FISH studies, etc), and single-gene targeted testing (Rauch et al., 2006; Shavell et al., 2003). Until the advent of more recent technologies (array CGH and next generation sequencing), these tools gave a diagnostic yield for children with GDD/ID in the region of 50–70% (Daily et al., 2000; Rauch et al., 2006). Therefore, up to half of children with GDD/ID remained undiagnosed.

‘Molecular karyotyping’ or ‘array Comparative Genomic Hybridisation’ (array CGH) is a technique that came into clinical practice across the UK during the first decade of the 21^st century (Rauch et al., 2006). Array CGH identifies sub-microscopic genetic imbalances across the genome. It can identify copy number variants (CNVs) in the number of genes present which may affect health or development. It allows much more detailed cytogenetic analysis and in most parts of the UK has become a first-line test, superseding traditional cytogenetic studies. In cases where traditional cytogenetic studies have not found a significant result, array CGH gives an average diagnostic yield of 10% (excluding variants of uncertain significance (VUSs)), and this yield rises to 14% for resolutions below 1 Mb (Rauch et al., 2006; Sagoo et al., 2009). As our knowledge advances, it is hoped the classification of VUSs will improve which could increase this diagnostic yield.

The Deciphering Developmental Disorders (DDD) study was a UK-based study sequencing the exomes of children with undiagnosed developmental disorders (Firth et al., 2011). Exomes are the coding regions of our genes, and account for about 1% of all our genetic material (Wang et al., 2013). The DDD study hoped that a molecular diagnosis could be found by comparison of a child’s exome with their parents’ (Firth et al., 2011). A diagnostic yield of 31% was reported from the first 1133 trios (children and both parents) recruited to the study, and 12 new developmental genes were discovered (Deciphering Developmental Disorders Study, 2015). An American-based study sequencing clinical exomes also found a diagnostic yield of 31% for trios, and 22% for proband-only cases (Lee et al., 2014). The diagnostic yield is expected to increase as new genes are described and further analysis takes place.

As genetic testing becomes more accessible and diagnostic rates increase, I wonder how this will affect the role of the Genetic Counsellor in supporting these families. Even though diagnostic rates will improve, there will undoubtedly be individuals who remain undiagnosed. In addition, there will be a growing number of individuals who are given a novel molecular diagnosis, about which very little may be known. While these families may receive answers to some of their questions, others will remain unanswered (such as information about prognosis and availability of peer-support from other families who have a child with the same condition). I wonder whether the role of the Genetic Counsellor is currently sufficient to meet the needs of these families, or whether adaptations to the role could better meet the need.

Support needs of families adapting to a child with a developmental disorder

Rosenthal et al. (2001) and Lewis et al. (2010) each conducted semi-structured interviews with parents of children with developmental disorders either in the USA (Rosenthal group) or the UK (Lewis group). The purpose of these studies was to find out what impact a lack of diagnosis had on parental adjustment and coping. There was a wide range in the length of time that parents had been aware of their child’s difficulties in both studies, which provides useful information about how coping and adaptation may change over time. Similar reactions to the initial recognition of a problem were reported by parents whether a child had a known diagnosis or not (Lewis et al., 2010). However, in the absence of a diagnosis, additional challenges were noted which could result in a longer period of adjustment and adaptation (Barnett et al., 2003; Heiman, 2002; Lewis et al., 2010; Rosenthal et al., 2001). These included having increased uncertainty about prognosis and a reduced ability to make life plans (e.g. whether their child had a reduced life expectancy, or whether they would be able to live independently as an adult). In addition, the number of investigations arranged, with the aim of seeking a diagnosis, could be both emotionally and physically draining.

A lack of diagnosis means there is greater uncertainty. Madeo et al. (2012) looked at the effect of uncertainty on parental coping and adaptation to raising a child with a developmental disorder. Lipinski et al. (2006) also looked at factors associated with parental uncertainty and perceived control, and the role they played in coping and adaptation for parents of children with a rare chromosome disorder (prevalence of 1/120,000 or lower), which provides useful information about families with novel or very rare conditions. Both studies used a mixed-methods survey (either paper or computer-based) and had relatively large sample sizes (266 and 363 respectively). Madeo et al. (2012) discussed that uncertainty can sometimes aid coping, as it leaves room for optimism of a positive outcome. However, in the majority of cases, both studies found that uncertainty perpetuated a feeling of lacking control over their child’s condition, which was linked to poorer coping and a longer process of adaptation, as reported by Rosenthal et al. (2001) and Lewis et al. (2010). Both Lipinski et al. (2006) and Madeo et al. (2012) found factors that were associated with lower perceived control were being less optimistic about the future and perceiving their child’s condition as more severe. Lipinski et al. (2006) found younger parents felt greater uncertainty but this was not replicated by Madeo et al. (2012), although the latter study population did not have a very wide age range. These studies help to explain why a lack of diagnosis, or the diagnosis of a very rare or novel condition, often results in an extended period of coping and adaptation and therefore why additional support may be appropriate.

As one parent from the Genetic Alliance UK patient charter commented “We always imagined that getting a diagnosis would be the final piece of the puzzle and the end of the journey, but it now feels as if we are at the very beginning of a new journey” (pg 9, Hazelton & Petchey, 2015). Another parent, whose child was found to have a unique unbalanced translocation, used the term ‘non-diagnosis’ as there was no prognostic information available and commented “It’s like being told something in a foreign language. It wasn’t a relief because I didn’t understand it” (pg 810, Lewis et al., 2010). For these parents the diagnosis had not brought all the answers they had hoped for.

An example seen through my own clinical practice was when I met parents of a 22 year old man with an overgrowth syndrome and moderate learning difficulties. He had been enrolled in the Childhood Overgrowth (COG) study run by the Institute of Cancer Research in the UK and recently identified as having a de novo pathogenic mutation is the gene DNMT3A. At the time the working name for this new syndrome was ‘DNMT3A overgrowth syndrome’ (Tatton-Brown et al., 2014) but is now called Tatton-Brown-Rahman syndrome (OMIM #615879). In clinic the parents had a strong emotional reaction to finally receiving a diagnosis. The mother commented that, with the lack of a diagnosis, it had always played on her mind whether the cause was due to something she had done during pregnancy, and finally she could put this ‘nagging doubt’ to rest. These parents asked what this meant for prognosis. The oldest reported individual from this study was 29, only 7 years older than this young man. With regards to prognosis, this can only be speculated based on the information already known about this gene. For DNMT3A, it is known to be one of the most commonly mutated genes in acute myeloid leukaemia. Therefore, the authors suggest there may be an increased cancer risk for individuals with a germline mutation, but further study is required to assess this. Although the parents had a very positive reaction to receiving a diagnosis, the uncertainties they were left with raised new questions and concerns which left them with an element of worry for the future. This exemplifies one of the key challenges for novel or rare diagnoses.

Parents described how the desire for a diagnosis diminished over time, as the child grew older, however often it never completely went away (Lewis et al., 2010; Rosenthal et al., 2001). In part, this may be due to becoming more familiar with their child’s condition as they grow, and forming a clearer idea of what the future may be like. It addition, this may be due to the realisation that a diagnosis will not change who their child is. However, there are times that re-kindle the desire for a diagnosis e.g. when the child is approaching adulthood and applying for additional support (e.g. supported housing), or when siblings are reaching reproductive age, and additional support could also be appropriate at these times.

The role of the Genetic Counsellor

Biesecker (pg 327, 2001) discussed the goals of genetic counselling and stated that “contemporary genetic counselling should strive to… facilitate clients’ ability to use genetic information in a personally meaningful way that minimises psychological distress and increases personal control”. Families are for the most part resilient, but the process of coping and adaptation still benefits from psychological support, regardless of whether a child receives a diagnosis or not (Barnett et al., 2003; Lewis et al., 2010). Seymour Kessler described two models of practice for Genetic Counsellors, a ‘teaching model’ and a ‘counselling model’ (Kessler, 1997). Kessler suggests that a hybrid approach is adopted incorporating elements of both so that the counselee has received the appropriate information but has also had time and space for discussion of the consequences and personal reflection. However, a number of studies have examined modern practice and found that the ‘teaching model’ is more often adopted, with the main purpose of information provision (Lerner et al., 2014; Meiser et al., 2008; Roter et al., 2006; Walser et al., 2017). Austin et al. (2014) reviewed the available literature and found that a ‘counselling model’ with the aim of addressing the psychosocial concerns, is reported to be associated with increased knowledge retention, reduced anxiety and higher satisfaction with decision-related outcomes. The authors go on to suggest that Genetic Counsellors focus more on this style in their practice. This is supported by Lipinski et al. (2006) who looked at the perceived helpfulness of genetic counselling, for parents of children with developmental disorders. The authors found that it was perceived as more helpful when parents were helped to increase a sense of perceived control over their child’s condition (Lipinski et al., 2006) which fits more with a ‘counselling model’ of practice. A study from the USA looking at the result-giving appointment of exome sequencing highlighted that these appointments were information-heavy and often missed opportunities to build relationships with patients (Walser et al., 2017). The counselling element tended to be neglected due to time restraints and so an on-going relationship with these families would be particular important, to improve understanding, reduce misconceptions, address frustration and disappointment, and improve satisfaction.

Genetic Counsellors have historically had the resources to offer long-term support to families in the UK. However, as demands on Genetic Services have increased, time restraints have limited the amount of contact Genetic Counsellors are able to offer families, and relationships have become shorter-term. Therefore, even though the need for support still exists, families may not request it as they may not recognise where this form of support is best sought (Lipinski et al., 2006). Genetic testing and genetic understanding is infiltrating many areas of healthcare, and the role of Genetic Counsellors as ‘information providers’ is becoming less specialised (Austin et al., 2014) however Genetic Counsellors have a unique set of skills and can play an important role in providing psychological support for families (Lipinski et al., 2006; Middleton et al., 2017). Austin et al. (2014) propose genetic counselling is remodelled “as a time-limited, highly circumscribed psychotherapeutic encounter”. Whereas there is some support for this (Wynn, 2016), in practical terms, due to increased demands and limited resources, from my own experience I feel there is doubt about whether this sort of service is viable in the UK at the moment. I would like to see the profession working towards this sort of model for families of children with developmental disorders and I describe below how this could look in practice.

Implications for Genetic Counselling practice

With the advancement of new genetic technologies described above, diagnostic rates will increase and families will receive more of the answers they seek. I see two key responsibilities for Genetic Counsellors in regards to advanced genetic testing. Firstly, in managing expectations about the limitations of genetic testing and secondly in identifying those families who could benefit from additional support and having the capacity to offer this.

Conclusion

In the age of advanced genetic technologies, expectations have never been higher about the diagnostic potential for individuals with developmental disorders. However, a diagnosis will not necessarily provide all of the answers sought. In addition, the search for a diagnosis could be hindering a family’s ability to accept their child’s condition. Without appropriate support, the process of coping and adaptation could be prolonged or even unsuccessful. It is important that Genetic Counsellors recognise the limitations of these new technologies and continue to support families irrespective of whether a diagnosis is made or not. Genetic Counsellors have the skills and opportunity to provide the support required to address the uncertainties families face, help identify areas where peer support can be found and increase perceived control, facilitating adaptation to improve individual and family functioning. Genetic Services in the UK may currently not have the resources to facilitate an extended support service such as this due to the demands they are already under, however I believe this type of service is the very essence upon which the Genetic Counselling profession was built and is in danger of being lost to the patients cost therefore should be fought for.