9q31.2 deletion (Weiss-Kruszka syndrome)

9q31.2 Deletion (Weiss-Kruszka syndrome)

chromosome 9

The 9q31.2 segment of the long arm of chromosome 9 contains the ZNF462 gene. Haploinsufficiency of this gene causes a well-recognized Weiss-Kruszka syndrome (WKS). While some individuals with WKS may only have mutations within the ZNF462 gene, there are a significant number of individuals with WKS that present due to 9q31.2 deletions¹. The term WKS is currently applied to both the patients with mutations in the ZNF462 gene and to patients with 9q31.2 deletions involving this gene.

ZNF462 is thought to play a role in embryonic development. Specifically, it is involved in the pluripotency and differentiation of embryonic stem cells by regulating the function of other genes. It is also thought to regulate neuronal development and the differentiation of neural cells².

Individuals with WKS often present with well-defined physical features including developmental delay with or without autism, growth delay, characteristic facial features, and some limb and structural abnormalities throughout the body.

A majority of reported patients with WKS, either due to deletion or mutations in ZNF426, have developmental delays (79%)³. These delays may manifest as delays in motor skills, speech, or global developmental delay. Roughly 33% of individuals have an autism spectrum disorder³. Additionally, delays in growth and microcephaly may also be seen, but these features are more frequently identified in those with deletions of the entire 9q31.2 region rather than those with mutations only including the ZNF462 gene⁴.

Those with WKS will frequently present with characteristic facial features. Most commonly, ptosis (83%), down slanting palpebral fissures (58%), wide philtrum (54%), arched eyebrows (50%), and a short upturned nose with a bulbous tip (46%) are seen in individuals³. Ear malformations including low set ears, inner ear malformations, prominent ears, and mildly cupped ears are also commonly identified³. Some patients may also present with hearing loss. It should be noted, however, that while these ear malformations are seen in roughly 50% of those with 9q31.2 deletions, hearing loss seems to be more common in those with deletions than those with mutations only including ZNF462⁴.

Although developmental delay and characteristic facial features are the most commonly identified features, there are some structural and limb abnormalities that have been previously identified in those with WKS. For example, heart defects including ventricular septal defect, bicuspid aortic valve, and left ventricular hypertrophy have been identified in 21% of individuals³. Dysgenesis of the corpus callosum can also be seen on imaging¹. Minor limb abnormalities such as single palmar crease, hypoplastic fingernails, small hands and feet, proximally placed thumbs, and fifth finger clinodactyly may also be seen³.

The clinical phenotype of WKS continues to expand as more patients with the condition are identified. It has become increasingly clear that a great deal of phenotypic heterogeneity may exist. More recently, it has been proposed that diabetes, certain cancers, and variants of the hypergonadotropic hypogonadism with anosmia (also called Kallmann Syndrome) may be related to the WKS clinical spectrum^2,5,6.

REFERENCES

¹Weiss K, Wigby K, Fannemel M, et al. (2017). Haploinsufficiency of ZNF462 is associated with craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay. Eur J Hum Genet. 25(8): 946–951.

²Pellino G, Chiasso L, Fiori G, et al. (2022). Acute lymphoblastic leukemia in a child with Weiss-Kruszka syndrome: Casual or causal association? Eur J Med Genet, 65(4): 104457.

³Kruszka P, Hu T, Hong S, et al. (2019). Phenotype delineation of ZNF462 related syndrome. Am J Med Genet A. 179(10): 2075–2082.

⁴Brady L, Ballantyne M, Duck J, et al.  (2023). Further characterization of the 9q31 microdeletion phenotype; delineation of a common region of overlap containing ZNF462. Mol Genet Genomic Med. 11(3): e2116.

⁵Li K, Chen X, Xiang L, et al. (2024). Diabetes in a Weiss-Kruszka syndrome boy and a de novo deletion in 9q31.2. Endocrine, 83(3): 824–825.

⁶Iivonen AP, Kärkinen J, Yellapragada V, et al. (2021). Kallmann syndrome in a patient with Weiss-Kruszka syndrome and a de novo deletion in 9q31.2. Eur J Endocrinol.  185(1): 57–66.