Meckel Gruber and Joubert Syndrome Diagnosed Prenatally: Allelism between the Two Ciliopathies, Complexities of...

Area of Science:

• Genetics
• Developmental Biology
• Medical Genetics

Background:

• Antenatal detection of occipital encephalocele and polycystic kidneys often indicates ciliopathies.
• Joubert syndrome and Meckel Gruber syndrome are common ciliopathies with significant genetic and phenotypic overlap.
• These overlapping features complicate accurate antenatal diagnosis and genetic counseling.

Purpose of the Study:

• To describe three cases of antenatally diagnosed occipital encephalocele and enlarged kidneys.
• To investigate the genetic underpinnings of these conditions using fetal autopsy, histopathology, and exome sequencing.
• To highlight the diagnostic challenges and limitations of preconceptional carrier screening in ciliopathies.

Main Methods:

• Detailed case reports of three fetuses with antenatal findings of occipital encephalocele and enlarged kidneys.
• Fetal autopsy and histopathological examination.
• Whole exome sequencing for genetic variant identification.

Main Results:

• Case 1: Meckel syndrome diagnosed with a novel nonsense variant in the CEP290 gene.
• Case 2: Joubert syndrome diagnosed via fetal exome sequencing, with parents identified as carriers for TMEM138 and SDCCAG8.
• Case 3: Meckel syndrome identified with digenic inheritance of a multiexon deletion in TMEM67 and KIF14.

Conclusions:

• Reported cases illustrate genetic heterogeneity in Meckel syndrome (novel variant, digenic inheritance) and Joubert syndrome.
• The findings underscore the limitations of preconceptional carrier screening for ciliopathies due to overlapping phenotypes.
• Advanced genetic testing like exome sequencing is crucial for accurate diagnosis in complex ciliopathies.