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Variable expressivity and incomplete penetrance in a large family with non‐classical Diamond‐Blackfan anemia associated with ribosomal protein L11 splicing variant
Author(s) -
Carlston Colleen M.,
Afify Zeinab A.,
Palumbos Janice C.,
Bagley Heidi,
Barbagelata Carlos,
WooderchakDonahue Whitney L.,
Mao Rong,
Carey John C.
Publication year - 2017
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.38360
Subject(s) - diamond–blackfan anemia , penetrance , anemia , short stature , genetics , medicine , family history , biology , pediatrics , gene , rna , phenotype , ribosome
Diamond‐Blackfan anemia (DBA) is a group of clinically and genetically heterogeneous bone marrow failure disorders with or without congenital anomalies. Variable expressivity and incomplete penetrance have been observed within affected families. Diamond‐Blackfan anemia‐7 (DBA7), caused by heterozygous mutations in ribosomal protein L11 ( RPL11 ), accounts for approximately 5% of DBA. DBA7 is usually characterized by early‐onset bone marrow failure often accompanied by congenital malformations, especially thumb defects. Here, we present the case of a 2‐year‐old boy with chronic mild normocytic anemia, short stature, bilateral underdevelopment of the thumbs, atrial septal defect, and hypospadias. Hematological testing revealed slightly decreased hematocrit and hemoglobin, normal HbF, and elevated eADA. Family history included maternal relatives with thumb defects, but the mother's thumbs were normal. Clinical exome sequencing detected a maternally‐inherited RPL11 variant, c.396+3A>G, that is predicted to affect splicing. A family correlation study of the identified variant demonstrates segregation with thumb anomalies in the mother's family. RNA studies suggest that the variant produces an alternative transcript that is likely susceptible to nonsense‐mediated decay. This report summarizes the prevalence of non‐anemia findings in DBA7 and describes a non‐classical familial presentation of DBA7 more associated with thumb anomalies than with anemia.