Private inherited microdeletion/microduplications: implications in clinical practice.
The introduction of array-CGH analysis is allowing the identification of novel genomic disorders. However, this new high-resolution technique is also opening novel diagnostic challenges when inherited private CNVs of unclear clinical significance are found. Oligo array-CGH analysis of 84 patients with mild to severe mental retardation associated with multiple congenital anomalies revealed 10 private CNVs inherited from a healthy parent. Three were deletions (7q31, 14q21.1, Xq25) and seven duplications (12p11.22, 12q21.31, 13q31.1, 17q12, Xp22.31, Xq28) ranging between 0.1 and 3.8Mb. Six rearrangements were not polymorphic. Four overlapped polymorphic regions to the extent of 10-61%. In one case the size was different between the proband and the healthy relative. Three small rearrangements were gene deserts. The remaining seven had a mean gene content of five (ranging from 1 to 18). None of the rearranged genes is known to be imprinted. Three disease-genes were found in three different cases: KAL1 in dupXp22.31, STS in another dupXp22.31 and TCF2 in dup17q12. The patient carrying the last duplication presents sex reversal, Peters' anomaly and renal cysts and the duplication is located 4Mb away from the HSD17B1 gene, coding a key enzyme of testosterone biosynthesis. Considering the overlap with polymorphic regions, size-identity within the family, gene content, kind of rearrangement and size of rearrangement we suggest that at least in five cases the relationship to the phenotype has not to be excluded. We recommend to maintain caution when asserting that chromosomal abnormalities inherited from a healthy parent are benign. A more complex mechanism may in fact be involved, such as a concurrent variation in the other allele or in another chromosome that influences the phenotype.
Mencarelli
Maria Antonietta
MA
Medical Genetics, Molecular Biology Department, University of Siena, Viale Bracci 2, 53100 Siena, Italy.
Katzaki
Eleni
E
Papa
Filomena Tiziana
FT
Sampieri
Katia
K
Caselli
Rossella
R
Uliana
Vera
V
Pollazzon
Marzia
M
Canitano
Roberto
R
Mostardini
Rosa
R
Grosso
Salvatore
S
Longo
Ilaria
I
Ariani
Francesca
F
Meloni
Ilaria
I
Hayek
Josef
J
Balestri
Paolo
P
Mari
Francesca
F
Renieri
Alessandra
A
D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D005260:Female; D017353:Gene Deletion; D020440:Gene Duplication; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007621:Karyotyping; D008297:Male; D009693:Nucleic Acid Hybridization; D010641:Phenotype