deletion mutation

**Definition:** Loss of genetic material, ranging from a single nucleotide to a whole chromosomal segment or gene.

**Types and consequences:** - **Small deletion, not a multiple of 3 (frameshift):** Shifts the reading frame downstream. This usually creates a premature stop codon (nonsense downstream), giving a truncated, nonfunctional protein that is often degraded by nonsense-mediated decay. It is typically a severe loss of function. Examples: Duchenne muscular dystrophy (frameshift or out-of-frame deletions of the DMD gene, which encodes dystrophin), Tay-Sachs disease (4-bp insertion in HEXA is a common frameshift; deletions also occur), and BRCA1/2 frameshift mutations. - **In-frame deletion (multiple of 3):** Removes one or more amino acids but keeps the reading frame. The protein may be partly functional. Examples: **ΔF508 in CFTR** (3-bp deletion removing phenylalanine 508, causing misfolding and ER degradation of CFTR; the most common cystic fibrosis mutation), and Becker muscular dystrophy (in-frame DMD deletions produce a shortened but partly functional dystrophin, so the disease is milder than Duchenne). - **Large (chromosomal) deletions:** Cause contiguous gene loss. - **Cri-du-chat syndrome:** 5p deletion. High-pitched cat-like cry, microcephaly, intellectual disability, VSD. - **Williams syndrome:** 7q11.23 deletion (includes the elastin gene). Elfin facies, supravalvular aortic stenosis, hypercalcemia, "cocktail party" personality, and strong verbal skills. - **DiGeorge (22q11.2 deletion) syndrome:** CATCH-22 (Cardiac defects, Abnormal facies, Thymic aplasia, Cleft palate, Hypocalcemia). - **Prader-Willi syndrome:** Paternal 15q11-q13 deletion (maternal imprinted and silenced). Hyperphagia, obesity, hypotonia, hypogonadism. - **Angelman syndrome:** Maternal 15q11-q13 deletion. Ataxia, seizures, inappropriate laughter ("happy puppet"). - **Others:** Wilms tumor (WAGR, 11p13), retinoblastoma (13q14 deletion of RB1), alpha-thalassemia (α-globin gene deletions: 1 deleted = silent carrier, 2 = trait, 3 = HbH disease, 4 = Hb Barts/hydrops fetalis), and AZF region Y-microdeletions (male infertility).

**Mechanisms:** Unequal crossing over during meiosis, errors in DNA replication (replication slippage), unrepaired double-strand breaks (non-homologous end joining), and unbalanced translocations or chromosomal breakage. Unequal crossing over between repetitive sequences causes many microdeletions.

**Clinical/testing pearls:** - Small deletions can be found by sequencing. Large deletions or microdeletions need **FISH**, array CGH (microarray), or MLPA. Standard karyotype detects only large deletions (about 5-10 Mb). - The **reading-frame rule** explains Duchenne (out-of-frame, severe) versus Becker (in-frame, milder). Dystrophin is X-linked recessive, and the Duchenne gene is the largest in the human genome. - Deletion of a tumor suppressor allele can uncover the remaining mutant allele (loss of heterozygosity, "second hit" in Knudson's two-hit hypothesis). - Compared with other point mutations: silent (same amino acid), missense (different amino acid), nonsense (premature stop). Frameshift mutations (insertions or deletions) usually have the most severe effect on protein function, after nonsense mutations near the start of the gene.