Congenital hydrocephalus: new Mendelian mutations and evidence for oligogenic inheritance

Table 1 Novel mutations in genes associated with hydrocephalus and confirmation of CRADD mutation

Patient ID	Gene	Zygosity	Inheritance	CADD score	Variant classification (ACMG)	Codes for classifying variants	Transcript variant description	Protein	Protein effect	Ethnicity	Ref
21	ARID1A	Het	De novo	40	P	PVS1, PS2 and PM2	NM_006015.4:c.6435delG	p.(Glu2145fs*54)	Frameshift	French
15.1; 15.2	CRADD	Hom	AR	24	LP	PS4, PM2 and PP3	NM_003805.3:c.509G > A	p.(Arg170His)	Missense	Finnish	[32, 40]
16.1; 16.2; 16.3	KIDINS220	Hom	AR	NA	LP	PS3, PM2, PM4 and PP1	NM_020738.2:c.2137_2145del	p.(Gln713_Leu715del)	Deletion	Pakistani	[43]
26	POMGNT1	Hom	AR	22.8	LP	PVS1 and PM2	NM_001243766.1:c.1539 + 1G > A	p.?	Splicing effect	Belgian
17	POMT2	Hom	AR	24.8	LP	PVS1 and PM2	NM_013382.5:c.333 + 1G > A	p.?	Splicing effect	Moroccan

The mutations are named according to HGVS nomenclature recommendation, with RefSeq identifier. All mutations are either absent in the homozygous state (CRADD, POMGNT1) or in both heterozygous and homozygous states (ARID1A, KIDINS220, POMT2) from ExAC and gnomAD databases. AR: autosomal recessive; Het: heterozygote; Hom: homozygote; NA: not applicable; P, pathogenic; LP, likely pathogenic; PVS1, null variant (nonsense, frameshift, canonical + / − 1 or 2 splice sites, initiation codon, single or multi-exon deletion); PS2, de novo (both maternity and paternity confirmed) in a patient with the disease and no family history; PS3, well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product; PS4, prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls; PM2, absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or ExAC; PM4, protein length changes due to inframe deletions/insertions in a non-repeat region or stop-loss variants; PP1, co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease; PP3, multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Classifications and codes following Ellard et al. 2020[58]

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