Genetic (Re-)evaluation to Optimize the Care of Adults With Intellectual Disability

In many cases, intellectual impairment associated with neurodevelopmental disorders (NDD) has a genetic cause (1). In the past, detection rates of 15–20% were achieved using molecular karyotyping (array technique). With the advent of exome sequencing (ES; Whole Exome Sequencing, WES; sequencing of all protein-coding DNA sequences), improved detection rates have become a reality, with national and international studies suggesting rates of about 30–50% in children (2, 3). To date, there have been only a few studies specifically investigating the detection rates of exome sequencing in adults with NDDs (4), and adults are commonly underrepresented in larger exome studies. Likewise, in everyday clinical practice, adult patients with a congenital intellectual disability, the cause of which could not be identified in childhood, are rarely (re)evaluated using human genetic testing; therefore, we have integrated such an evaluation into the structure of the assessment performed at the Medical Treatment Center for Adults with Intellectual Disabilities and/or Severe Multiple Disabilities (MZEB) at the Aachen University Hospital. With this approach, it was possible to obtain detection rates and to evaluate the impact of identifying the cause of a NDD on further medical care.

Methods

From 1 November 2018, when the MZEB opened, to 31 October 2021, 628 patients were seen for MZEB assessment; of these, 438 patients (69.7%) had previously been diagnosed with intellectual disability. As part of the collaboration between the MZEB and the Institute for Human Genetics and Genomic Medicine at the Aachen University Medical Center, patients with intellectual disability and uncertain diagnosis were offered a human genetic consultation. Over the study period, 60 patients (aged between 19 and 60 years; 26 female, 34 male) took up the offer of a genetic step-by-step diagnosis (array analysis, exome sequencing, in case of evidence of fragile X syndrome supplemented by FMR1 repeat testing). Thirty-one patients (51.7%) had already undergone genetic testing in the past, including microscopic chromosome analysis (n = 26), array analysis (n = 15), FMR1 gene analysis (n = 12), and single-gene analysis (n = 10), among others. The pathogenicity of the variants identified using exome sequencing were generally classified according to the consensus recommendations of the American College of Medical Genetics and Genomics (ACMG) (5). All patients and legal guardians were informed verbally and in writing about the genetic diagnostic evaluation in accordance with the German Genetic Diagnostics Act (GenDG). Data analysis was performed under the principles of the Declaration of Helsinki; written informed consent to participate in the registry study for evaluation of the treatment at the MZEB (EVALMZEB, EK 044/19) was available from all patients.

Results

In 38 of the 60 (63.3%) adults, at least one causal genetic change was identified. In nine (15%) of the studied patients, a pathogenic copy number variation (CNV) was already identified at the step of array analysis (Table). In 29 (48.3%) of the studied patients, pathogenic sequence variants were detected in a disease gene which was known at the time of evaluation. Overall, there was high heterogeneity with 34 different genetic disease entities, including some very rare conditions. Eight disease-causing variants were identified in genes for which less than ten cases of adult patients had been published in the literature so far. For twelve genes with identified changes, disease association in humans had been demonstrated not earlier than during the last decade.

Table

The results of genetic testing

Causal diagnosis had a direct impact on clinical management in 26 of the 38 diagnosed patients (68.4%). For example, nine patients (23.7%) did not require MRI examination (n = 6), muscle biopsy (n = 2) or spinal tap (n = 1) under anesthesia. In 17 patients (44.7%), specific screening examinations or specific monitoring could be derived from the identified cause: advice on medications to be preferred (n = 4) or avoided (n = 2) with the disease, monitoring of cognitive decline with specific recommendations for daily living (n = 6), and diagnosis-guided specialist referral (n = 9). Five patients (13.2%) were offered disease-specific therapy (n = 3, ketogenic diet, galactose-free diet, enzyme replacement therapy) or an attempt to pharmacologically treat the condition (n = 2, intranasal insulin), whereas in two patients drug therapy initiated based on a different suspected diagnosis was discontinued. In two patients, it was possible to provide relief from concerns about an increased risk of tumor development assumed based on the diagnosis that was initially suspected on the grounds of clinical findings. With the detection of a de novo mutation or de novo chromosomal abnormality, it was possible in 22 patients (36.7% of all patients or 57.9% of solved cases) to provide immediate relief from the concerns of other relatives about a recurrence of the disease in their own offspring.

Discussion

In a high percentage (63.3%) of the assessed adults with intellectual disability, a genetic diagnosis could be established, thus ending a “diagnostic odyssey” having often spanned several decades. The recommendations for an adaption/change of clinical management resulting from the genetic diagnoses in 68.4% of patients show that in adult patients with a NDD, which could not be definitely diagnosed in childhood, genetic (re-)evaluation is warranted. The detection rates of comprehensive genetic testing in adults with congenital intellectual disability obtained in our study are comparable with those reported in various national and international studies in pediatric populations (2, 3). Future larger studies will allow further insights into detection rates among adults with NDDs and even more precise statements on their benefit for clinical management. However, it can already be concluded that in many cases the diagnostic possibilities of modern sequencing techniques are still underutilized in this patient group.

In our experience, genetic testing, including exome sequencing and, in the future, genome sequencing, can be easily integrated into the medical care of this patient group as an early diagnostic step in an MZEB‘s routines. At the MZEB, molecular diagnosis often offers an immediate benefit for patients, facilitates medical care, and enables the structured monitoring of previously poorly known long-term courses of rare genetic diseases.

Cordula Knopp, Robin Steiner, Eva Lausberg, Caroline von Hoegen, Sabine Busse, Robert Meyer, Katja Eggermann, Herdit Schüler, Matthias Begemann, Thomas Eggermann, Ingo Kurth, Jörg B. Schulz, Miriam Elbracht*, Andrea Maier*

Conflict of interest statement
The authors declare that no conflict of interest exists.

Manuscript received on 11 May 2022, revised version accepted on 19 August 2022.

Cite this as:
Knopp C, Steiner R, Lausberg E, von Hoegen C, Busse S, Meyer R, Eggermann K, Schüler H, Begemann M, Eggermann T, Kurth I, Schulz JB, Elbracht M, Maier A: Genetic (re-)evaluation to optimize the care of adults with intellectual disability.

Dtsch Arztebl Int 2022; 119: 895–6. DOI: 10.3238/arztebl.m2022.0312

References

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5. Richards S, Aziz N, Bale S, et al.: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405–23