Case report of a boy with NCDN associated neurodevelopmental disorder

We present the case of a nine year old boy with severe neurodevelopmental delay and epilepsy. He was born in the 40th week of pregnancy by cesarean section with normal birth measurements (body length 52 cm (41 P., -0.22 SD), head circumference 35 cm (32 P., -0.46 SD), body weight 3180 g (16 P., -1.01 SD)). He showed severe developmental delay, secondary microcephaly and plagiocephaly, epilepsy, hypothyroidism, growth hormone deficiency, and sleep disorders. He learned to crawl at around 5 years of age. Currently, he is wheelchair-bound, but he has been able to pull himself up using a walker and walk short distances since his 8th birthday. He is nonverbal, but he can form simple syllables and communicate with a few simple gestures. Additionally, a complex heart defect was diagnosed postnatally with perimembranous VSD, PDA, PFO, and persistent superior vena cava with opening into the coronary sinus. At the age of 4 months, he underwent surgical correction. He also showed bilateral hip subluxation due to hip dysplasia. A cranial MRI performed at 2 years of age suspected bilateral subependymal heterotopias lateral to the posterior horn. Dysmorphic findings were deep set eyes, coarse facies, broad upper incisor, malformed ears with broad helix and big concha. Anamnestically, both parents have a significant intellectual disability but were both not available for genetic testing. Single short read whole genome sequencing revealed a likely pathogenic heterozygous missense variant in NDCN (NM_014284.3:c.1598C>T (p.Pro533Leu)). Heterozygous missense variants in the NCDN gene have already been described as causative for an autosomal dominant developmental disorder with epilepsy (MIM: #619373). This neurological developmental disorder with epilepsy in childhood (NEDIES) is characterized by the occurrence of severe and frequent epileptic seizures within the first year of life. Affected individuals exhibit mild to severe global developmental delay with delayed (to non-acquired) walking and poor or absent speech development. While the NDCN variant therefore contributes the neurodevelopmental phenotype of our patient, his complex heart defect still remains unexplained.