1 - Serviço de Genética Médica, Hospital Dona Estefânia, Centro Hospitalar Universitário Lisboa Central, Lisboa, Portugal
2 - Centro de Genética Preditiva e Preventiva, Instituto de Biologia Molecular e Celular, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Annual Meeting Sociedade Portuguesa de Genética Humana 2022 (Poster)
Background: Koolen-de Vries Syndrome (KdVS; OMIM #610443) is a clinically heterogeneous disorder with autosomal dominant inheritance, caused by a 17q21.31 microdeletion encompassing KANSL1 gene in 95% of cases. Heterozygous pathogenic variants in KANSL1 gene are responsible for less than 5% of the cases. KdVS is characterized by neonatal hypotonia, developmental delay, intellectual disability, facial dysmorphisms. friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies.
Case presentation: We report an 11-year-old (yo) girl, first child of a nonconsanguineous couple, born at 40th week of gestation, pregnancy complicated by oligoamnios. At birth, weight was at 25th centile, length at 14th centile and head circumference at 42nd centile. At 12-months-old, she was referred to our outpatient clinic due to failure to thrive, development delay and hypothyroidism. At observation, she presented a triangular face, epicanthus, bulbous nasal tip, protruding ears, long philtrum, brachydactyly and small umbilical hernia. At 2yo, she presents short stature (-2.2 SD), strabismus, no speech, abnormal gait and accentuated coarse facial features. At 9yo, she has moderate intellectual disability, seizure, myopia and prognathism. Brain MRI revealed hypopituitarism, with adenohypophysis hypoplasia and ectopic neurohypophysis. Karyotype and chromosomal microarray analysis were normal. Exome Sequencing analysis revealed a heterozygous likely pathogenic variant c.(2666+1_2667-1)_(2724+1_2725-1)del at KANSL1 gene.
Conclusions: KANSL1 gene haploinsufficiency causes KdVS and to the best of our knowledge, we hereby firstly describe this novel KANSL1 variant, associated with less common features of KdVS, including hypopituitarism and hypothyroidism, contributing to a broader genotype-phenotype correlation related to KdVS. This case report also shows the importance of exome sequencing in dysmorphic patients with intellectual disability, and a normal karyotype and microarray, increasing the diagnostic yield and allowing proper genetic counselling to the families.
Palavras Chave: Development delay, KANSL1, Koolen-de Vries Syndrome, genotype-phenotype correlation