Comprehensive genomic analysis identifies a diverse landscape of sideroblastic and non-sideroblastic iron related anemias with novel and pathogenic variants in an iron deficient endemic setting

The history for the 5 CMA cases are as follows:-

1. HMA-2 :- 0.6 month male child presented with poor feeding and noted to have mild-moderate pallor. CBC showed Hemoglobin 9.0gm/dl, MCV- 58fl, MCH 17.3, MCHC 29, Iron 113 ug/dl, Ferritin 297 ug/l, TSAT-45%, TIBC-297 ug/dl, Hepcidin- 20.3ng/ml. No transfusions received and antenatal and neonatal history uneventful. HPLC (both parents), alpha sequencing normal. Targeted NGS shows a heterozygous VUS in GLRX5 gene along with a VUS in BMP6 gene. WES- Does not add anything further significant.

2. HMA-3 :- 0.8 month male child with transfusion dependent microcytic hypochromic anemia and neurological developmental delay. Expired at 1 year of age due to secondary infection (acinetobacter and toxoplasmosis). Hb- 6.5, MCV-61.5, MCH-18.3, Iron 45 ug/dl, Ferritin 650. Targeted panel and WES - negative.

3. HMA-4:- 5 year male child with severe microcytic hypochromic anemia and received just one transfusion outside. Has microcephaly and SNHL. Hb 5, MCV- 56, MCH- 18, MCHC- 23, Iron- 75, Ferritin - 330, TIBC- 290, TSAT- 41%. Targeted NGS and WES show a Homozygous VUS in BMP6 gene (? association?) 

4. HMA-6:- 2 year old male child with moderate microcytic hypochromic anemia and focal seizures. Hb -8, MCV- 58, MCH- 16, MCHC-27, Iron- 94, Ferritin -380, Transferrin levels- 10 (very low). Targeted NGS and WES show a single heterozygous VUS mutation in TF gene and another intrinsic rare variant but reported in pop. Database (could it make it compound her for atransferrinemia?) 

5. HMA-7:- 7 year male child with short stature, consanguinity in family, moderate macrocytic anemia with HB-7, MCV-113, Iron-55, Ferritin -209, TSAT-54%. Also Bone marrow shows coarse vacuolations in erythroid cells (12%) and 19% RS. Suspicion PMS- But MLPA for mitochondrial genome normal, no deletions. Targeted panel NGS and WES reveal a heterozygous VUS in LARS2 gene (? nature).