Novel compound heterozygous FAM20C variants cause Raine syndrome – retrospective prenatal diagnosis and literature review

Raine syndrome, RS, (OMIM 259775) is a rare autosomal recessive disorder with prevalence of less than 1:1 000 000, caused by homozygous or compound heterozygous variants in FAM20C gene. A retrospective genetic investigation was performed on DNA extracted from amniotic cell cultures previously used for cytogenetic studies. Extracted DNA was used for aCGH (array comparative genomic hybridization) and Sanger sequencing. Parental blood samples were tested for karyotype (GTG – G-banding using trypsin and Giemsa) and molecular karyotype (aCGH). Additionally, paternal sample was tested by NGS (next generation sequencing). We present two fetal cases of Raine syndrome. Both were compound heterozygotes for two FAM20C gene variants: a maternally-inherited copy-number loss encompassing exons 1-3 (arr[GRCh37] 7p22.3(170366_229852)x1) and a paternally-inherited novel frameshift exon 1 variant [NM_020223.4:c.307_308dupTC p.(Ser104ArgfsTer27)]. Prenatal phenotype associated with Raine syndrome often includes characteristic pattern of intracranial calcification, osteosclerosis and facial dysmorphism. However, in majority of cases, diagnosis is made postnatally. It is therefore important to report all cases of Raine syndrome for which USS (ultrasound scan) findings are available – this will enable better understanding and detection of RS prenatally.