Table 3.
Cases with VUS that were predicted as inherited by the algorithm (n = 8 of 51)
| ID | Cluster | Sex | Age | Clinical diagnosis | Zygosity | Germ line variant | TL (flow-FISH) | Patient clinical features | Decision making |
|---|---|---|---|---|---|---|---|---|---|
| NIH024 | 1 | F | 10 | MAA | X-linked | DKC1; c.915+10G>A | <First | Dystrophic nails and abnormal lung testing. Maternal grandfather with thrombocytopenia, pulmonary fibrosis, and early hair graying. Mother with early hair graying. | Variant's pathogenicity needs to be confirmed with functional assays. Extended screening with WES/WGS is also recommended. |
| NIH214 | 1 | M | 8 | MAA | Het | TERT c.1324G>A; p.Asp442Asn | <First | No family history or signs of inherited disease. | The TERT variant is likely the cause of patient’s disease. |
| NIH258 | 1 | M | 17 | Isolated thrombocytopenia | Het | RTEL1: c.2507C>G; p.Pro836Arg | <First | Thrombocytopenia since age 11, development delay, lymphopenia, short tongue frenulum, syndactyly of the second and third digit right foot, microcephaly, shallow forehead, short stature, micrognathia, and almond shaped eyes. Also with splenomegaly, pulmonary obstructive disease, and atrioventricular septal defect repaired as infant. Cousins with thrombocytopenia and enlarged spleen, improved after splenectomy. | Patient’s phenotype is not consistent with an AD telomere disease. This variant is likely benign. Extended screening with WES/WGS is recommended |
| NIH259 | 1 | M | 69 | MAA | Het | MECOM: c.2720A>G; p.Asn907Ser | <First | Long-standing thrombocytopenia and history of non-Hodgkin lymphoma. Both father and 2 sons with thrombocytopenia. | The MECOM variant is likely the cause of patient’s disease. Screening of affected family members can confirm variant's pathogenicity. |
| NIH326 | 1 | M | 32 | MAA | Het |
TERT: c.383C>T; p.T128I |
<First | With splenomegaly. Cousin with thrombocytopenia and uncle died of cirrhosis at age of 60. | The TERT variant is likely the cause of patient’s disease. |
| NCI 456-1 |
2 | F | 5 | Isolated neutropenia | Het |
TERT: c.3158G>A; p.Gly1053Glu |
<First | Cytopenias at age of 2, multiple warts, and mild nail dystrophy. | The TERT variant is likely the cause of patient’s disease. |
| NIH324 | 2 | M | 48 | Isolated anemia | Het | TERT; c.2786 C>T; p.P929L | <First | Cytopenias since age 18, hepatopulmonary syndrome with s/p liver transplant, and interstitial pneumonitis. Father died of cirrhosis at age of 52 and brother had AA at age of 14. | The TERT variant is likely the cause of patient’s disease. |
| USP063 | 2 | M | 1 | Isolated neutropenia | Biallelic |
USB1 c.477A>C; p.Q159H/ c.344G>A; p.R115K |
Normal | Microcytic anemia, and no megakaryocytes and erythroid precursors in bone marrow biopsy. No skin alterations and normal IgG and IgM, but low IgA. Strong family history of immunodeficiency; 3 brothers died months after birth due to severe immunodeficiency. | Patient's family history is not consistent with an AR disease, though disease possible. Extended screening with WES/WGS is recommended |
AD, autosomal dominant; AR, autosomal recessive; Ig, immunoglobulin; WES, whole-exome sequencing; WGS, whole-genome sequencing.