Two Novel FAM20C Variants in a Family with Raine Syndrome

Abstract

Two siblings from a Mexican family who carried lethal Raine syndrome are presented. A newborn term male (case 1) and his 21 gestational week brother (case 2), with a similar osteosclerotic pattern: generalized osteosclerosis, which is more evident in facial bones and cranial base. Prenatal findings at 21 weeks and histopathological features for case 2 are described. A novel combination of biallelic FAM20C pathogenic variants were detected, a maternal cytosine duplication at position 456 and a paternal deletion of a cytosine in position 474 in exon 1, which change the reading frame with a premature termination at codon 207 and 185 respectively. These changes are in concordance with a negative detection of the protein in liver and kidney as shown in case 2. Necropsy showed absence of pancreatic Langerhans Islets, which are reported here for the first time. Corpus callosum absence is added to the few reported cases of brain defects in Raine syndrome. This report shows two new FAM20C variants not described previously, and negative protein detection in the liver and the kidney. We highlight that lethal Raine syndrome is well defined as early as 21 weeks, including mineralization defects and craniofacial features. Pancreas and brain defects found here in FAM20C deficiency extend the functional spectrum of this protein to previously unknown organs.

Raine syndrome: Prenatal diagnosis based on recognizable fetal facial features and characteristic intracranial calcification

“…So far, no clear relation between the type or location of variants and disease severity has been identified. However, based on our observation, the cases reported and the recent family described by Hernández-Zavala et al, 41 we can suggest that the biallelic proteintruncating mutations were associated with a severe and lethal RS. This was also evident in the two cases with lethal phenotype and have large chromosomal deletions encompassing the entire FAM20C…”

“…Prenatal diagnosis of RS is challenging as most of the patients reported with RS were discovered retrospectively after postnatal diagnosis of the syndrome showing the specific facial dysmorphic features as flat facial profile, hypoplastic nose, and prominent eyes, in addition to intracerebral calcification. 5,9,23,38,41 Thirty-five lethal cases (including this report) 1,3,5-7,21-41 and 22 non-lethal cases with significant variability in the severity have been reported. [8][9][10][11][12][13][14][15][16][17][18][19][20] In our series, we highlight our experience with the prenatal detection of three lethal RS that was suspected as early as the 22 weeks of gestation following the detection of the characteristic craniofacial dysmorphic features, osteosclerosis, and ectopic calcification in the brain and other organs.…”

“…52,53 Interestingly, two of our cases had cerebellar hypoplasia, an apparently uncommon finding that was not previously reported prenatally but detected by postnatal CT assessment in a single lethal case reported by Seidahmed et al 6 Agenesis of corpus callosum, encephalocele, cortical atrophy, and pachygyria were infrequent additional findings that have been reported previously in two lethal cases, as well as two non-lethal cases. 4,7,17,22,41 T A B L E 1 Prenatal ultrasound findings and measurements in our reported cases with Raine syndrome Polyhydramnios was detected in all our cases and was found retrospectively in almost all the cases of RS. This is probably linked to the prenatal onset of swallowing difficulties caused by micrognathia and cleft palate.…”

“…In fact, homozygous truncating mutations in the FAM20C gene have not been described before in any patient with RS. Only, Hernández-Zavala et al41 reported two Mexican sibs with lethal RS carrying two F I G U R E 2 (A) Portion of the sequencing electropherogram showing the three novel FAM20C pathogenic variants identified in our study. (B) A schematic diagram of the FAM20C showing the domains, exons, and all reported pathogenic variants.…”

Identification of Novel MeCP2 Cancer-Associated Target Genes and Post-Translational Modifications

“…We found that MeCP2 binds to genes in MCF7 cells in regions where CpG methylation had been mapped such as SDK1, a cell adhesion molecule; Jagged 2 (JAG2), a Notch ligand; glycogenin 2 (GYG2), an enzyme involved in glycogen synthesis ( Figure 1C , Figure S1C ). These novel MeCP2 targets as well as others in Figure S1 had not previously been linked with MeCP2, but have been linked with pathobiology associated with cancer ( 76 – 84 ) or genetic disorders such as Leigh syndrome ( 85 ) and Raine syndrome ( 86 , 87 ). We also found that MeCP2 binds to genomic regions devoid of CpG methylation such as for USP34, MGAM, GMDS, SLC45A4, SSU72, CAPN2 and PLXN2 ( Figures S1B–C ).…”