The long way to a MED13L-associated diagnosis - clarity about recurrence risks after three decades

We present the case of a 39-year-old man with intellectual disability and mild facial dysmorphism. He works as a gardener in an integrative institution and lives in a group of people with special needs. Speaking only a few words, his verbal understanding is good. He is good at orientation and memory and transfers independently between known locations by bike.
Born spontaneously after 40 weeks with a weight of 2120g (P3, -1.96z), length 48cm (<P1, -2.8z), head circumference 32cm (<P1, -3.7z), APGAR 9/10/10, the neonatal period was complicated by feeding difficulties and a unilateral herniotomy at the age of 2 months. He learned walking with 18 months and first words at the age of 3-4 years. In our genetics department, he first presented at the age of 4y with developmental delay (developmental age 1,5y at the age of 3y), strabism, brachydactyly, clinodactyly V, epicanthus, upslanted palpebral fissures, and normal body measurements. At the age of 11y he had a seizure, the EEG showed slow waves temporo-occipital, cranial MRIs were unremarkable (1996 and 2006). After a first clinical suspicion of Down syndrome, chromosomal analyses were performed from lymphocyte culture and fibroblast culture from skin biopsy, retrieving normal 46,XY karyotypes. Subsequently, fra-X critical region in FMR1 showed a normal length (1999). Later, FISH-analysis from buccal mucosa retrieved no sign of trisomy 21, CGH-array retrieved normal results (2009).
After his healthy half-sister was pregnant with her third child and worried about the possibility of an X-chromosomal cause, their common mother suggested to reinvestigate the case. We initiated duo-exome sequencing with mother and index, since the father remains unavailable for genetic testing. We identified a pathogenic variant in MED13L in the index and not the mother, resulting in a very low risk for his half-sister’s offspring.