BLOOM SYNDROME

A number of human genetic disorders cause chromosomal breakage,
which is characterized by genome instability. Genome instability is
associated with immune deficiency, a predisposition to develop cancer,
and premature aging . Mutations in the BLM or RECQL3 gene located on
chromosome 15 which encodes a DNA helicase in the RecQ family cause Bloom
syndrome. The RecQ family is highly conserved and plays crucial roles as
genome caretakers. Mutations in three RecQ genes BLM, RECQL4, and WRN,
are responsible for Bloom syndrome. The BLM gene encodes a BLM helicase
which forms a complex with two other proteins, DNA topoisomerase IIIα and
RMI. DNA helicases are involved in the replication and repair of DNA. Bloom’s
is typically characterised by short stature, photosensitivity, telangiectatic
erythema, learning difficulties, immunodeficiency and malignancy. Abnormal
DNA exchange takes place between sister chromatids and results in
genetic instability that may lead to cancer, especially lymphoma and
acute myelogenous leukemia, lower and upper gastrointestinal tract
neoplasias, cutaneous tumors, and neoplasias in the genitalia and
urinary tract. Individuals with BSyn have a mean of 40-100 sister chromatid
exchanges per metaphase (normal SCEs: <10 per metaphase). Increased
frequency of SCEs is demonstrable in BSyn cultured cells (including
lymphocytes, fibroblasts, and amniocytes) recently it was discovered
BRAFT and FANCM protein complexes that link BS and Fanconi
anemia. Bloom's is largely dependent on cytogenetic analysis. In gene
structure a 4,528-bp codan sequence defines BLM, which contains a long open
reading frame encoding a 1,417-amino-acid protein BLM. BLM comprises 22
exons and is located at chromosome band 15q26.1.

It is more common in the Eastern European Jewish (Ashkenazi)
population with a carrier rate for the Ashkenazi mutation of
approximately 1 percent.Bloom Syndrome is an autosomal recessive
genetic disorder caused by a mutation in the BLM gene, which codes for
the DNA repair enzyme RecQL3 helicase.

Analysis of mRNA and microRNA (miRNA) expression in fibroblasts from
individuals with Bloom syndrome and in BLM-depleted control fibroblasts.
Differentially expressed mRNAs are connected with cell proliferation, survival,
and molecular mechanisms of cancer, and differentially expressed miRNAs
target genes involved in cancer and in immune function. These pathways can
contribute to the proportional dwarfism, elevated cancer risk, immune
dysfunction, and other features observed in Bloom syndrome individuals. BLM
binds to G-quadruplex (G4) DNA, and G4 motifs were enriched at transcription
start sites (TSS) and especially within first introns of differentially expressed
mRNAs in Bloom syndrome compared with normal cells, which suggested that
G-quadruplex structures formed at these motifs are physiologic targets for
BLM. mRNAs and miRNAs that can drive the pathogenesis of Bloom syndrome.
Testing approaches can include a combination of gene-targeted
testing (single-gene testing,  multi gene panel )
and comprehensive genomic testing ( exome sequencing  genome
sequencing) depending on the phenotype.In single-gene testing
sequence analysis of BLM detects small intragenic deletions/insertions
and missense, nonsense, and splice site variants; typically, exon or
whole-gene deletions/duplications are not detected. Perform sequence
analysis first. If only one or no pathogenic variant is found, perform
gene-targeted deletion/duplication analysis to detect intragenic deletions
or duplications. Exome sequencing is most commonly used; genome
sequencing is also possible. Genome sequencing Sequence analysis of
the genome including coding and noncoding regions typically performed
by next-generation sequencing (NGS) of sheared genomic DNA

References
 Kamenisch Y, Berneburg M. Progeroid syndromes and UV-induced oxidative
DNA damage. J Investig Dermatol Symp Proc 2009; 14:8.
 Wissem Hafsi; Talel Badri. Bloom Syndrome (Congenital Telangiectatic
Erythema)  November 8, 2019
 Arora et al., 2014, Int J Dermatol, 53(7):798-802, PMID: 24602044
 Giang Huong Nguyena,b,1, Weiliang Tangc,1, Ana I. Roblesa,1, Richard P. Beyerd ,
Lucas T. Graye , Judith A. Welsha , Aaron J. Schettera , Kensuke Kumamotoa,f, Xin
Wei Wanga , Ian D. Hicksonb,g, Nancy Maizelse , Raymond J. Monnat, Jr.c,h,2, and
Curtis C. Harrisa,2 2014
 Maeve Flanagan, BA1 and Christopher M Cunniff, MD, FACMG2 Created: March 22,
2006; Updated: February 14, 2019.

 Sanz et al., 2013, http://www.ncbi.nlm.nih.gov/books/NBK1398/

 Rajni Vekaria,1 Ree’Thee Bhatt,2 Ponnusamy Saravanan,1,3 Richard C de Boer4
 Flanagan M, Cunniff CM. Bloom Syndrome. In: GeneReviews [Internet],
Adam MP, Ardinger HH, Pagon RA, et al (Eds), University of Washington,
Seattle 2019.