Beyond Asymptomatic Carriers: Clinical Burden of a KDM5C Female Patient

A 14-year-old female patient has been followed in paediatric neurology clinic since the age of 6 due to language delay. She is the first child of healthy, non-consanguineous parents from Tangier; family history is unremarkable, and her two siblings are healthy. Pregnancy was uneventful, delivery occurred at term, and there were no neonatal complications. In the first years of life, only a delay in language acquisition and comprehension was remarkable, whereas motor and social milestones were age-appropriate. During follow-up, a cognitive disorder became evident; the patient exhibited immature behavior, emotional lability, poor information retention, and perseverative speech. She currently attends a special education program; she remains unable to read and requires assistance for all activities of daily living. Behavioral disturbances with episodes of aggression have emerged, necessitating psychiatric follow-up and treatment with risperidone and methylphenidate.

On examination, minor dysmorphic features were noted: hypertrichosis, synophrys, bulbous nose with elongated columella, diastema, and inverted nipples. Neurological exam revealed only mild signs of pyramidal involvement, being otherwise normal.

Extensive complementary studies were unremarkable, including otolaryngologist evaluation, metabolic panel, cranial MRI, EMG, and chromosomal microarray (aCGH). Clinical exome sequencing identified a de novo likely pathogenic variant in KDM5C (c.577dupC:p.(His193*)), consistent with X-linked Claes-Jensen intellectual disability syndrome.

This clinical case illustrates that, although many female carriers of pathogenic KDM5C variants are asymptomatic, some may present clinical manifestations that significantly affect their daily functioning.