Biallelic variants in NUDCD2 associated with a multiple malformation syndrome with cholestasis and renal failure.

NudC-like protein 2 (NUDCD2) is a 4-exon protein-coding gene at 5q34. The protein appears to act in concert with other genes regulating cell migration and microtubule extension. Early studies in model organisms show associations with LIS1, HERC2, and cohesin subunits via a co-chaperone function with Heat shock protein 90 (Hsp90). It is a candidate gene for human pathology. We present two unrelated patients with biallelic variants in NUDCD2. Their phenotypes comprise similar dysmorphic facies, midline brain hypoplasia, hypothyroidism, pulmonary and aortic valve stenosis, severe dysfunction of the liver and kidneys, profound hypotonia, and early death. The cellular analysis demonstrates the absence of the NUDCD2 protein in fibroblasts of one patient with biallelic loss-of-function variants. The data suggest that NUDCD2 deficiency causes this recognizable syndrome that has features of a ciliopathy with additional complications.

A 9.8 Mb deletion at 7q31.2q31.31 downstream of FOXP2 in an individual with speech and language impairment suggests a possible positional effect.

Haploinsufficiency of FOXP2 causes FOXP2-related speech and language disorder. We report a 9.8 Mb deletion downstream of FOXP2 in a girl with speech and language impairment, developmental delay, and other features. We propose involvement of FOXP2 in pathogenesis of these phenotypes, likely due to positional effects on the gene.