Fig. 3. The phenotype associated with ZNF699 homozygous loss-of-function (LoF) variants.

Upper panel: photographs showing phenotypic features of two patients (patients 27 and 35, Table 1). Patient 27, male index has low anterior hairline, thick scalp hair, thick eyebrows, synophrys, long eyelashes, long palpebral fissures, proptosis, strabismus, bulbous nose, low hanging columella, smooth philtrum, wide mouth, micrognathia, short neck, brachydactyly, right preaxial polydactyly, and bilateral syndactyly of the second and third toes. Patient 35, male index with coarse face, broad eyebrows, long palpebral fissures, wide mouth, thin vermilion of the upper lip, and bilateral absent thumbs. He presented generalized hypotonia and was severely emaciated. The patient deceased at 9 months old. Lower panel: summarized family trees of patients with ZNF699 homozygous LoF variants and clinical features. Patients presented with a severe phenotype that included congenital heart defects, gastrointestinal (intestinal atresia, pyloric stenosis, GER, hepatosplenomegaly), genitourinary (renal hypoplasia, cryptorchidism, chordee, hypospadias, ambiguous genitalia), and skeletal abnormalities (preaxial polydactyly, absent thumbs, syndactyly). Other recurrent features were generalized hypotonia, sensorineural hearing impairment, and premature hair graying. All patients have severe neurodevelopmental delay (NDD).