Clinical Features
The syndrome caused by pathogenic and likely pathogenic variants in the ZEB2 gene is a multisystem disorder named Mowat-Wilson syndrome (MWS) and characterized by distinctive facial features (hypertelorism, wide eyebrows with irregularity in the middle part, prominent columella, prominent or pointed chin and raised earlobes with a central depression), microcephaly, congenital heart defects with a prevalence of septal defects, abnormalities of the pulmonary arteries and / or valves, Hirschsprung disease or chronic constipation, eye and genitourinary abnormalities (particularly hypospadias in males) and complete or partial agenesis of the corpus callosum. Affected individuals have moderate to severe intellectual disability. Expressive language is often limited to a few words or is absent, with relative retention of receptive language skills, but there are some rare individuals whose language skills are much better developed. Epilepsy with a characteristic clinical evolution and EEG pattern is also common. Basic growth parameters (weight, length or height, head circumference) are often normal at birth, but have a tendency to drop below the normal range during childhood and adolescence. Most of the affected children have a serene, affectionate and generally happy demeanor. An increased pain threshold should be taken into account.
Prevalence
The prevalence of MWS has been estimated at between 1:50,000 and 1:70,000 live births.
Genetic Counselling
MWS is an autosomal dominant disorder associated with the Zinc finger homeobox 1 B (ZEB2) gene, located on chromosome 2q22, which codes for transcription factor ZEB2 (also known as ZFHX1B, SMADIP1, or SIP1). It can be caused by a pathogenic variant within ZEB2, a heterozygous deletion of 2q22.3 involving ZEB2, or, rarely, a chromosome rearrangement that disrupts ZEB2. Almost all individuals reported to date have a de novo genetic alteration; rarely, recurrence in a family has been reported when a parent has a low level of somatic or presumed germline mosaicism for a MWS-causing pathogenic variant. Once the causative genetic variant has been identified in the proband, prenatal testing may be offered to parents of a child with MWS because of the recurrence risk associated with the possibility of parental mosaicism or a balanced chromosome rearrangement.
ZEB2