The clinical presentation of most early-onset neurological disorders is ambiguous due to their heterogeneous manifestation and symptom non-specificity (1). In recent years, genetic testing has become a useful diagnostic tool for identifying genetic mutations associated with rare neurological disorders. However, even Whole Exome Sequencing (WES) – a technique which allows for analysis of all exons in a patient’s genome – often results in the identification of multiple genetic variants which may potentially explain a patient’s complex clinical picture. In such cases, segregation analysis becomes an indispensable method for clarifying the significance of the variants. The diagnostic process is further complicated if one of the parents is not available for segregation analysis, which is the case in
In the following case study, we present a patient with a complex neurological syndrome with accompanying facial abnormalities, who was conceived through IVF with donor sperm. Via analysis of the WES data one heterozygous genetic variant in the
The Ephrin Receptor A4 (
A 2-year-old Caucasian male was referred to our laboratory for genetic clarification of a non-specified neurological syndrome with developmental delay and facial abnormalities. The case history revealed that the patient was conceived via IVF with sperm from an unidentified Caucasian donor. The mother was healthy with no neurological disorders or genetic abnormalities, and there were no complications during pregnancy and birth (patient birth weight and height – 3490g and 50cm, respectively).
Anamnesis revealed that at approximately 4 months of age the patient’s condition started deteriorating as indicated by delayed psychomotor, cognitive, and visual development. At around the same time, the patient started suffering from grand-mal seizures. At approximately 7 months of age, the patient already exhibited severe drug-resistant epilepsy, significant psychomotor retardation despite physiotherapy, limb hypertonia, loss of pupillary light response, and nearly complete loss of visual acuity, which rendered him effectively blind. He also exhibited peculiar dysmorphic facial features with hypertelorism, micrognathia, and unusually low auricles. During the following 5 months he suffered a number of additional medical complications including abnormal elevation of Vitamins B1 and B12, pneumonia, and anemia, some of these complications led to hospitalization.
Although the patient’s epilepsy and eye abnormalities have continued to aggravate, multiple neurological and ophthalmological examinations have revealed no apparent cause of the patient’s complex medical state. Furthermore, subsequent metabolic and biochemical blood tests were negative for lysosomal enzymes, Very Long Chain Fatty Acids (VLCFA), amino acids and acylcarnitines, and 3-OMethyldopa (3-OMD). A dry blood spot test for Neuronal Ceroid Lipofuscinosis (NCL) was also negative. Initial genetic testing has shown a normal karyotype, no mutations in a targeted 341 gene retinal degeneration-related panel, and no mutations in the mitochondrial genome. Following from the patient’s increasingly worsening condition and the absence of any effective treatment, he was referred for WES in hopes of determining his diagnosis.
After a detailed explanation of all procedures, a written informed consent was obtained from the patient’s mother, and all described medical procedures and analyses were conducted in accordance with the Declaration of Helsinki and the ethical guidelines of Medical University Sofia. The Ethics Committee of Medical University Sofia has approved this study.
A blood sample was taken from the patient and subjected to DNA extraction by standard salting-out procedure (7). WES was performed and the patient’s genetic profile was analyzed via the GenesearchNGS software (Phenosystems). The detected variants were interpreted with respect to their pathogenicity following the recommendations of the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) (8). Direct Sanger sequencing was performed with BigDye® Terminator cycle sequencing kit v.3.1 (Applied Biosystems, Foster City, CA, USA) for confirmation of the WES findings and for Segregation analysis in order to determine the variants’ inheritance. Due to the ethical standards of IVF with donor sperm, no genetic analyses of the biological father were possible.
We identified a heterozygous frameshift variant c.1655_1656del, p.(Ser552CysfsTer23) in the
Mutations in the
MetaDome (9) indicates that the identified
Moreover, the genetic variant is not found in the gnomAD v2.1.1 controls and
Recently, a number of