Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ

Abstract

Congenital microcephaly is the clinical presentation of significantly reduced head circumference at birth. It manifests as both non-syndromic—microcephaly primary hereditary (MCPH)—and syndromic forms and shows considerable inter- and intrafamilial variability. It has been hypothesized that additional genetic variants may be responsible for this variability, but data are sparse. We have conducted deep phenotyping and genotyping of five Pakistani multiplex families with either MCPH (n = 3) or Seckel syndrome (n = 2). In addition to homozygous causal variants in ASPM or CENPJ, we discovered additional heterozygous modifier variants in WDR62, CEP63, RAD50 and PCNT—genes already known to be associated with neurological disorders. MCPH patients carrying an additional heterozygous modifier variant showed more severe phenotypic features. Likewise, the phenotype of Seckel syndrome caused by a novel CENPJ variant was aggravated to microcephalic osteodysplastic primordial dwarfism type II (MOPDII) in conjunction with an additional PCNT variant. We show that the CENPJ missense variant impairs splicing and decreases protein expression. We also observed centrosome amplification errors in patient cells, which were twofold higher in MOPDII as compared to Seckel cells. Taken together, these observations advocate for consideration of additional variants in related genes for their role in modifying the expressivity of the phenotype and need to be considered in genetic counseling and risk assessment.

Separation of function mutations in microcephaly protein CPAP/CENPJ, reveal its role in regulating centriole number and length

“…Although the G-box domain does not interact directly with tubulin, previously reported primary microcephaly (MCPH6) missense mutations E1235V in the G-box is known to increase centriole length (MCPH6) (Bond et al , 2005; Kitagawa et al , 2011a) via an unknown mechanism. Recently, another primary microcephaly mutation in the G-box domain has been mapped, which substitutes aspartic acid at 1196 amino acid position with the uncharged asparagine (Makhdoom et al , 2021). However, the effect of D1196N mutation on CPAP function remains to be tested.…”

“…Specific mutations separating these two functions of CPAP would be a powerful tool to investigate mechanisms dictating this cross-talk between the centriole size and length. Recently another microcephaly mutation has been mapped in the G-box of CPAP, which resulted in missense mutation D1196N (Makhdoom et al , 2021). However, it is unknown how this would affect CPAP function and lead to microcephaly.…”

ASPM and TROAP gene expression as potential malignant tumor markers

“…Multiple transcript variants of this gene encoding different isoforms have been found. Therefore, this gene regulates the cell proliferation cycle, and the disorder caused by its high expression may cause the cell to eventually become cancerous (39,40). A previous study reported ASPM's cancer-promoting effects but did not confirm its status as an oncogene.…”

Genetic Primary Microcephalies: When Centrosome Dysfunction Dictates Brain and Body Size

“…ASPM is the most frequently mutated gene in autosomal recessive PMs. Since the identification of the first patients [ 6 ], 861 individuals from 390 families carrying 210 different biallelic variants spread over the gene have been reported (for synthesis, see [ 50 , 51 ] and more recently [ 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ]). Approximately 55% of published cases were of Pakistani origin.…”

“…A high proportion of this group of patients comes from consanguineous families. It remains unclear whether ASPM mutations alone cause epilepsy without MCD or whether additional variants in other PM- or epilepsy-causing genes exacerbate the phenotype, as shown by Duerincks et al and Makhdoom [ 62 , 66 ], underlying variabilities between patients or siblings. Finally, although this question remains unaddressed, the loss of normal excitatory–inhibitory neuronal balance in the cerebral cortex of patients carrying ASPM mutations may also explain the high rate of epilepsy in patients without MCD.…”