A number sign (#) is used with this entry because of evidence that Weiss-Kruszka syndrome (WSKA) is caused by heterozygous mutation in the ZNF462 gene (617371) on chromosome 9q31.

Weiss-Kruszka syndrome (WSKA) is an autosomal dominant multiple congenital anomaly syndrome characterized by variable but usually mild global developmental delay and common craniofacial abnormalities, including ptosis, abnormal head shape, downslanting palpebral fissures, epicanthal folds, arched eyebrows, and short upturned nose. Many patients have hypotonia and feeding difficulties. A few patients show agenesis of the corpus callosum on brain imaging. Most cases occur sporadically, but there are rare familial cases that show highly variable expressivity in the phenotypic manifestations (summary by Kruszka et al., 2019).

Weiss et al. (2017) reported 4 members of a 4-generation family and 3 additional unrelated patients with an overlapping congenital syndrome. The family consisted of 2 sisters, aged 2 and 4 years, their father, and paternal grandmother; a paternal great-grandfather of the sisters was also reportedly affected. All had an abnormal head shape with craniosynostosis/metopic ridging, a pointed forehead, and variable dysmorphic facial features, including ptosis, downslanting palpebral fissures, arched eyebrows, epicanthal folds, short upturned nose with bulbous tip, and marked cupid's bow with wide philtrum. Brain imaging showed agenesis of the corpus callosum only in the 2-year-old sister, who was the proband; this abnormality was detected on prenatal ultrasound at 18 weeks' gestational age. None of the affected family members had developmental delay. The 3 additional unrelated children had similar dysmorphic features to those observed in the family, but these patients also had mild global developmental delay with mildly delayed walking, speech delay, and/or autism spectrum disorder. Only 1 of the 3 (patient 3) had a hypoplastic corpus callosum and mild ventriculomegaly; this boy also had transposition of the great vessels, patent ductus arteriosus, feeding difficulties requiring tube feeding, and dysplastic ears.

Kruszka et al. (2019) reported 14 unrelated patients, ranging in age from 7 months to 15 years, with a similar disorder. The patients were diagnosed by whole-exome or whole-genome sequencing in multiple research and commercial labs, and 9 were found through GeneMatcher. All except 2 patients had some degree of global developmental delay, often with mildly impaired intellectual development and speech delay. Two had a formal diagnosis of autism spectrum disorder and 4 had attention deficit/hyperactivity disorder; most patients of appropriate age were able to attend special schooling. All patients had at least some dysmorphic facial features, including ptosis, downslanting palpebral fissures, arched eyebrows, epicanthal folds, hypertelorism, short upturned nose with bulbous tip, cupid's bow or wide philtrum, retrognathia, small mandible, cleft palate, and low-set or abnormal ears. Three had craniosynostosis or metopic ridging, and a few had plagiocephaly or dolichocephaly. Nine patients had feeding difficulties, sometimes requiring tube feeding, 7 had hypotonia, and 2 had hearing loss. Brain imaging, performed in 8 patients, showed agenesis of the corpus callosum only in 1 and normal findings in 7. Two patients had congenital heart defects, 2 had fifth finger clinodactyly, and a few had additional defects, such as cryptorchidism or umbilical hernia, but these features were not assessed or not reported in all patients.

The transmission pattern of WSKA in the family reported by Weiss et al. (2017) was consistent with autosomal dominant inheritance with variable expressivity.

In 4 affected members of a 4-generation family (family 1) with WSKA, Weiss et al. (2017) identified a heterozygous nonsense mutation in the ZNF462 gene (R1263X; 617371.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family with evidence of variable expressivity. Three additional unrelated patients with a similar phenotype were found to carry de novo heterozygous mutations in the ZNF462 gene (see, e.g., 617371.0002-617371.0003). Functional studies of the variants and studies of patient cells were not performed, but all of the variants were predicted to result in a loss of function and haploinsufficiency. The authors noted that the ZNF462 gene is highly conserved in most mammals and is intolerant of loss-of-function variants based on databases of genetic variation.

In 14 unrelated patients with WSKA, Kruszka et al. (2019) identified heterozygous loss-of-function mutations in the ZNF462 gene (see, e.g., 617371.0004-617371.0007). Most of the mutations occurred de novo, but there was 1 instance of paternal transmission from a father who had surgery for ptosis and another instance of maternal transmission from an unaffected mother who was mosaic for the mutation. Most of the mutations occurred in exon 3, which makes up 54% of the coding region. Functional studies of the variants and studies of patient cells were not performed, but all were predicted to result in ZNF462 haploinsufficiency.