FamilyName: Kar 2018 Family 1

FamilyPresentingHPOs: HP:0001249, HP:0000508, HP:0010442

FamilyNotHPOs:

CountryOrigin: India

Ethnicity:

Race: Asian

FamilyPreviousTesting: Authors stated that homozygosity mapping did not identify any significant CNVs. Loss of heterozygosity (greater than 1kb) were observed over all affected siblings in shromosome 2, 7, 10, and 14. The Chromosome 2q had a 11Mb region with 141 genes, of which none were associateed with ID, ptosis, and polydactyly together.

FamilyMethod1:

FamilyMethod2:

FamilyGenotypingMethod: Homozygosity mapping, using SNP array analysis ( Illumina Human-CytoSNO-12v2.1. DNA) on the entire family (including parents), and exome sequencing in all the siblings. All mutations were confirmed by Sanger sequencing in the proband, parents, siblings (affected and unaffected) and a control was used. WES identified mutations in the UGT1A7 gene (c.654A>C) within the shared chromosome 2 region, as well as ARMC( (c.879G>A). They also found mutations in the gene ZFPM1 (c.1331_1339delinsCCC), but this was not within any shared region of homozygosity between the siblings. Neither UGT1A7 or ZFPM1 is associated with a disease/ phenotype per OMIM.

Affected: 3

Unaffected: 1

Segregations:

PublishedLOD: n/a

eLOD: 1.32

AddSegregationInfo: Family is consanguineous.

ProbandLabel: Kar 2018 Family- II:1, male

Variant: NM_025139.5(ARMC9):c.879G>A (p.Thr293=)

ClinVar: 522606

gnomAD: MAF (Ash-JEw)= 0.0001022, no homozygotes

FamilyAddInfo:

FamilyPMIDs:

CasePresenting HPOs: HP:000148, HP:0000494, HP:0000316, HP:0000311, HP:0000218, HP:0030084, HP:0001182, HP:0006369, HP:0002761, HP:0005880, HP:0006253, HP:0004322, HP:0007068, HP:0002419

VariantEvidence: The ARMC9 c.879G>A synonymous mutation is the last base in exon 9 (of 21 total exons) and is predicted to alter splicing. ARMC9 was transcribed into the pCAS2 minigene system and expressed in COS7 cells. RT-PCR of the transfected cells showed skipping of exon 9 in the mutant (Mt) cells compared to ARMC9 wildtype (Wt) cells that retained exon 9 (Figure 2). Sanger sequencing of the ARMC9-pCAS_Mt vector showed a 99 base pair deletion of exon 9 (Supplementary Figure 1), which is a loss of 33 amino acids encoded by exon 9. Exon 9 of ARMC9 encodes part of the ARM Domain 1 which is highly conserved among several speciies. Structural modeling indicates that the loss of the 33 amino acids (aa261-293) would critically disrupt the structure of ARMC9 ( Figure 3).