Variant identification using whole exome sequencing in a family suspected with Iron-refractory Iron Deficiency Anaemia
Iron-refractory iron deficiency anaemia (IRIDA) is a rare type of anaemia that affects about 1 in 1 million people globally. The inheritance pattern is autosomal recessive, which is caused by a defective Transmembrane Protease Serine 6 (TMPRSS6) gene. Patients with TMPRSS6 variants exhibit microc...
| Main Authors: | , , , , , , , , |
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| Format: | Conference or Workshop Item |
| Language: | English |
| Published: |
UPM
2024
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| Online Access: | http://psasir.upm.edu.my/id/eprint/116509/ http://psasir.upm.edu.my/id/eprint/116509/1/116509.pdf |
| _version_ | 1848867021167525888 |
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| author | Karuppiah, Thilakavathy Mohamed Ibrahim, Noor Haliza Musa, Nurul Huda Shankar, Aissvarya Ahmad Asnawi, Asral Wirda Yap, Mandy Yee Yee Sathar, Jameela Selvaratnam, Veena Noor Alif Wira, Nurul Ain Suraya |
| author_facet | Karuppiah, Thilakavathy Mohamed Ibrahim, Noor Haliza Musa, Nurul Huda Shankar, Aissvarya Ahmad Asnawi, Asral Wirda Yap, Mandy Yee Yee Sathar, Jameela Selvaratnam, Veena Noor Alif Wira, Nurul Ain Suraya |
| author_sort | Karuppiah, Thilakavathy |
| building | UPM Institutional Repository |
| collection | Online Access |
| description | Iron-refractory iron deficiency anaemia (IRIDA) is a rare type of anaemia that affects
about 1 in 1 million people globally. The inheritance pattern is autosomal recessive, which
is caused by a defective Transmembrane Protease Serine 6 (TMPRSS6) gene. Patients
with TMPRSS6 variants exhibit microcytic hypochromicity, low serum iron and
transferrin saturation (TSAT), relatively low serum ferritin, normal to high hepcidin, and
unresponsive to oral iron. Based on our knowledge, no genetic studies have been
conducted on IRIDA in Malaysia. This study aims to describe the molecular genetic
findings in a family suspected of IRIDA using whole exome sequencing (WES). Two male
siblings with persistent and unexplained anaemia and three male family members who
were not having symptoms were recruited for this study at the Anaemia Clinic, Hospital
Ampang. DNA was extracted from blood samples and sent for WES service.
Bioinformatic analysis was performed to identify the presence of gene variants related to
IRIDA. Gennext software (Version: 0.1.0) was utilised for variant annotation, and
various databases were used for the variant filtering and prioritisation process such as
NCBI, OMIM, HPO, etc. Haematological parameters revealed that the two suspected
sons had microcytic hypochromic anaemia, low haemoglobin and TSAT, and normal
serum hepcidin. The proband had low serum iron and normal ferritin, while the other
suspected son had relatively low serum iron and ferritin. All the other three male family
members showed normal haematological parameters. Pathogenic variants were not found
in the family members; however, common SNPs related to IRIDA were identified. All
five family members carried homozygous TMPRSS6/rs855791
(NM_001289000.1:c.2246T>C) and SLC11A2/rs445520 (NM_001174130.2:c.17A>C).
The two suspected siblings carried heterozygous TMPRSS6/rs2235324
(NM_001374504.1:c.730A>G) but not the TMPRSS6/rs78174698
(NM_001374504.1:c.1636C>T) that was found in the father and first son. In addition, the
proband was found to carry a homozygous splice-site deletion variant,
TMPRSS6/rs60484081 (NM_001374504.1:c.1842-6_1842-2delCTGGGG). The
haematological parameters of the suspected siblings point towards the IRIDA phenotype.
rs78174698 was reported to increase serum ferritin, whereas the absence of this variant
probably reduces serum ferritin in the suspected siblings, an indication of IRIDA.
rs60484081 could be a modifier SNP that causes reduced penetrance in the proband,
showing less severe symptoms compared to his brother. These findings emphasised that
WES can be used in diagnosing underlying IRIDA that affect this family. Thus,
advancements in diagnostic tools help families in need get better treatment for IRIDA. |
| first_indexed | 2025-11-15T14:29:52Z |
| format | Conference or Workshop Item |
| id | upm-116509 |
| institution | Universiti Putra Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-15T14:29:52Z |
| publishDate | 2024 |
| publisher | UPM |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | upm-1165092025-04-09T07:02:10Z http://psasir.upm.edu.my/id/eprint/116509/ Variant identification using whole exome sequencing in a family suspected with Iron-refractory Iron Deficiency Anaemia Karuppiah, Thilakavathy Mohamed Ibrahim, Noor Haliza Musa, Nurul Huda Shankar, Aissvarya Ahmad Asnawi, Asral Wirda Yap, Mandy Yee Yee Sathar, Jameela Selvaratnam, Veena Noor Alif Wira, Nurul Ain Suraya Iron-refractory iron deficiency anaemia (IRIDA) is a rare type of anaemia that affects about 1 in 1 million people globally. The inheritance pattern is autosomal recessive, which is caused by a defective Transmembrane Protease Serine 6 (TMPRSS6) gene. Patients with TMPRSS6 variants exhibit microcytic hypochromicity, low serum iron and transferrin saturation (TSAT), relatively low serum ferritin, normal to high hepcidin, and unresponsive to oral iron. Based on our knowledge, no genetic studies have been conducted on IRIDA in Malaysia. This study aims to describe the molecular genetic findings in a family suspected of IRIDA using whole exome sequencing (WES). Two male siblings with persistent and unexplained anaemia and three male family members who were not having symptoms were recruited for this study at the Anaemia Clinic, Hospital Ampang. DNA was extracted from blood samples and sent for WES service. Bioinformatic analysis was performed to identify the presence of gene variants related to IRIDA. Gennext software (Version: 0.1.0) was utilised for variant annotation, and various databases were used for the variant filtering and prioritisation process such as NCBI, OMIM, HPO, etc. Haematological parameters revealed that the two suspected sons had microcytic hypochromic anaemia, low haemoglobin and TSAT, and normal serum hepcidin. The proband had low serum iron and normal ferritin, while the other suspected son had relatively low serum iron and ferritin. All the other three male family members showed normal haematological parameters. Pathogenic variants were not found in the family members; however, common SNPs related to IRIDA were identified. All five family members carried homozygous TMPRSS6/rs855791 (NM_001289000.1:c.2246T>C) and SLC11A2/rs445520 (NM_001174130.2:c.17A>C). The two suspected siblings carried heterozygous TMPRSS6/rs2235324 (NM_001374504.1:c.730A>G) but not the TMPRSS6/rs78174698 (NM_001374504.1:c.1636C>T) that was found in the father and first son. In addition, the proband was found to carry a homozygous splice-site deletion variant, TMPRSS6/rs60484081 (NM_001374504.1:c.1842-6_1842-2delCTGGGG). The haematological parameters of the suspected siblings point towards the IRIDA phenotype. rs78174698 was reported to increase serum ferritin, whereas the absence of this variant probably reduces serum ferritin in the suspected siblings, an indication of IRIDA. rs60484081 could be a modifier SNP that causes reduced penetrance in the proband, showing less severe symptoms compared to his brother. These findings emphasised that WES can be used in diagnosing underlying IRIDA that affect this family. Thus, advancements in diagnostic tools help families in need get better treatment for IRIDA. UPM 2024 Conference or Workshop Item PeerReviewed text en http://psasir.upm.edu.my/id/eprint/116509/1/116509.pdf Karuppiah, Thilakavathy and Mohamed Ibrahim, Noor Haliza and Musa, Nurul Huda and Shankar, Aissvarya and Ahmad Asnawi, Asral Wirda and Yap, Mandy Yee Yee and Sathar, Jameela and Selvaratnam, Veena and Noor Alif Wira, Nurul Ain Suraya (2024) Variant identification using whole exome sequencing in a family suspected with Iron-refractory Iron Deficiency Anaemia. In: 14th Malaysian Symposium of Biomedical Science 2024, 1-2 Jun 2024, Universiti Putra Malaysia, Serdang. (p. 40). |
| spellingShingle | Karuppiah, Thilakavathy Mohamed Ibrahim, Noor Haliza Musa, Nurul Huda Shankar, Aissvarya Ahmad Asnawi, Asral Wirda Yap, Mandy Yee Yee Sathar, Jameela Selvaratnam, Veena Noor Alif Wira, Nurul Ain Suraya Variant identification using whole exome sequencing in a family suspected with Iron-refractory Iron Deficiency Anaemia |
| title | Variant identification using whole exome sequencing in a family suspected with Iron-refractory Iron Deficiency Anaemia |
| title_full | Variant identification using whole exome sequencing in a family suspected with Iron-refractory Iron Deficiency Anaemia |
| title_fullStr | Variant identification using whole exome sequencing in a family suspected with Iron-refractory Iron Deficiency Anaemia |
| title_full_unstemmed | Variant identification using whole exome sequencing in a family suspected with Iron-refractory Iron Deficiency Anaemia |
| title_short | Variant identification using whole exome sequencing in a family suspected with Iron-refractory Iron Deficiency Anaemia |
| title_sort | variant identification using whole exome sequencing in a family suspected with iron-refractory iron deficiency anaemia |
| url | http://psasir.upm.edu.my/id/eprint/116509/ http://psasir.upm.edu.my/id/eprint/116509/1/116509.pdf |