Families

What is it?
This is a newly described genetic disorder caused by homozygous (biallelic) loss-of-function mutations in the WDR83OSgene. The gene encodes a small protein called Asterix, which works with another protein (CCDC47) in a complex that helps other proteins fold properly inside cells. This complex is especially important for proteins that sit in cell membranes.

Main Clinical Features
Affected individuals typically show a combination of neurological and liver-related symptoms, including:

Neurological Symptoms
•    Developmental delay: Most children show delays in motor milestones (e.g., sitting, walking) and speech.
•    Intellectual disability: Ranges from moderate to severe.
•    Hypotonia: Reduced muscle tone.
•    Autistic features: Poor eye contact, weak social interaction.
•    Seizures: In some cases.

Facial dysmorphism:Despite there is wide variety in facial characteristics, common features include: Prominent philtrum (groove between nose and upper lip), everted lower lip, open or tented mouth, ptosis (drooping eyelids), hypo- or hypertelorism (abnormal spacing between eyes), synophrys (joined eyebrows)

Liver and Gastrointestinal Symptoms
•    Hypercholanemia: Elevated bile acids in the blood.
•    Intractable itching (pruritus): Often severe and persistent.
•    Hepatomegaly: Enlarged liver.
•    Gallstones
•    Feeding difficulties
•    Fat malabsorption: Leading to poor growth and gastrointestinal issues like diarrhea or constipation.

Inheritance Pattern:The disorder follows an autosomal recessive inheritance pattern. Both parents of affected individuals are typically carriers (have one copy of the mutated gene but are healthy). Most affected individuals come from consanguineous families (parents are related), although cases have also been found in non-consanguineous families.

Prevalence:This is an ultra-rare disease, with only 14 affected individuals identified across nine unrelated families from diverse regions including Turkey, Saudi Arabia, Iran, Morocco, Ethiopia, and Eritrea. It is likely underdiagnosed, especially in populations with high rates of consanguinity.

Diagnosis: Diagnosis is made through genetic testing, specifically exome sequencing, which identifies mutations in the WDR83OSgene. Liver function tests may show elevated bile acids but normal bilirubin and liver enzymes, distinguishing it from other liver diseases.

Research Insights
•    Studies in zebrafish models confirm that loss of WDR83OSaffects:
•    Brain development
•    Facial structure
•    Fat absorption
•    These findings support the gene’s role in both neurological and liver function.