Table 4.

Genes and Disorders of Interest in the Differential Diagnosis of Fanconi Anemia

Gene(s)DisorderMOIChromosome BreakageClinical Characteristics
ATM Ataxia-telangiectasia (A-T)ARCells derived from persons w/A-T may exhibit high rates of spontaneous chromosome breakage.Progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis, conjunctival telangiectasias, immunodeficiency, frequent infections, ↑ risk for malignancy, hypersensitivity to ionizing radiation
ATR
CENPJ
CEP152
CEP63
DNA2
NIN
NSMCE2
RBBP8
TRAIP 		Seckel syndrome (OMIM PS210600)ARMay show ↑ chromosome breakage w/DNA cross-linking agents 1 (MMC, DEB)Growth deficiency, microcephaly w/ID, characteristic facial appearance; may be assoc w/pancytopenia &/or AML
BLM Bloom syndrome (BSyn)ARCells derived from persons w/BSyn may exhibit high rates of spontaneous chromosome breakage.Severe pre- & postnatal growth deficiency, immune abnormalities, sensitivity to sunlight, insulin resistance, high risk for many cancers that occur at an early age
NBN Nijmegen breakage syndrome ARMay manifest ↑ chromosome breakage w/MMCShort stature, progressive microcephaly w/loss of cognitive skills, premature ovarian failure in females, recurrent sinopulmonary infections, ↑ risk for cancer (esp lymphoma)
NF1 Neurofibromatosis 1 ADNot assoc w/↑ chromosome breakageMultiple café au lait spots, axillary & inguinal freckling, multiple cutaneous neurofibromas, iris Lisch nodules, choroidal freckling
RBM8A 2 Thrombocytopenia absent radius syndrome ARNot assoc w/chromosome breakageBilateral absence of the radii w/presence of both thumbs & thrombocytopenia that is generally transient

AD = autosomal dominant; AR = autosomal recessive; DEB = diepoxybutane; FA = Fanconi anemia; ID = intellectual disability; MMC = mitomycin C; MOI = mode of inheritance

1.
2.

The diagnosis of thrombocytopenia absent radius syndrome is confirmed by identification of a null heterozygous allele (most often a minimally deleted 200-kb region at chromosome band 1q21.1, but in some cases a heterozygous RBM8A pathogenic variant detected by molecular genetic testing) in trans with a heterozygous RBM8A hypomorphic allele.

From: Fanconi Anemia

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