Craniofacial (the most consistent and recognisable feature set):
● Ptosis (approximately 83%): the single most consistent feature.
● Downslanting palpebral fissures (approximately 54%).
● Exaggerated Cupid's bow (approximately 54%).
● Arched, often high, eyebrows (approximately 50%).
● Epicanthal folds (approximately 46%).
● Short, upturned nose with a bulbous tip (approximately 46%).
● Metopic ridging or craniosynostosis, involving the metopic or lambdoid suture (approximately 38%).
Neurodevelopment:
● Developmental delay in more than 75%, typically mild; speech delay is most common (approximately 42%), followed by motor delay (approximately 38%).
● Hypotonia in approximately 50%, contributing to motor delay.
● Autism spectrum disorder in approximately one third.
● Seizures have not been reported in any affected individual to date.
Ears and hearing:
● External ear anomalies and/or hearing differences in approximately 45%: low-set ears (approximately 25%); structural anomalies (prominent, cupped or overfolded ears, ear pits, horizontal crus of the helix); hearing loss of varying severity and type in a minority.
Gastrointestinal and feeding:
● Feeding difficulties in approximately 50%: gastro-oesophageal reflux (occasionally requiring fundoplication), laryngomalacia, dysphagia, eosinophilic oesophagitis, and oral-motor problems. A subset require gastrostomy.
Cardiac:
● Congenital heart defects in approximately 21%: ventricular septal defect, bicuspid aortic valve, transposition of the great arteries, and patent ductus arteriosus.
Central nervous system (structural) and limbs:
● Corpus callosum abnormalities in approximately 25% (initially thought to be a major feature, but the proportion has fallen as milder cases are ascertained).
● Minor limb anomalies in approximately 25%: single palmar crease, fifth-finger clinodactyly.
Growth and emerging associations (single reports, phenotype expansion):
● Short stature and growth hormone deficiency.
● Genital anomalies, including cryptorchidism (reported in a small number of males).
● Congenital diaphragmatic hernia (first reported in 2025/2026; not previously recognised).
● Hypogonadotropic hypogonadism / Kallmann syndrome and cleft lip/palate in the context of larger contiguous 9q31.2 deletions (attributable to co-deleted neighbouring genes rather than ZNF462alone).
● A single report of association with childhood-onset systemic lupus erythematosus (causal relationship unconfirmed).
There is no established genotype-phenotype correlation. Deep phenotyping with facial-analysis tools (GestaltMatcher) shows a high degree of facial similarity across the reported cohort, supporting a recognisable gestalt.
ZNF462