Familial complex 3q;10q rearrangement unraveled by subtelomeric FISH analysis

Abstract

In recent years, subtelomeric rearrangements have been identified as a major cause of multiple congenital anomalies/mental retardation syndromes. Currently, more than 2,500 individuals with mental retardation have been tested and reported in whom subtelomeric rearrangements were detected ranging from 2% to 29%. Therefore, subtelomeric FISH analysis is indicated as a second tier test after high-resolution G-banding analysis in patients with otherwise unexplained developmental delay/mental retardation and/or multiple congenital anomalies. We describe a patient and her three maternal female cousins, all showing an undiagnosed MCA/MR syndrome, associated with the same complex subtelomeric rearrangement. Subtelomeric FISH testing performed between 3(1/2) and 18 years after the initial karyotype showed, in all four patients, distal trisomy 3q and distal monosomy 10q as follows: 46,XX,ish der(10)t(3;10)(q29;q26.3)mat(D10S2488+,D10S2490-, D3S1272+,D10Z1+). Parental subtelomeric FISH analysis showed that the proposita's mother and three of four brothers and one of two sisters had a cryptic balanced 3:10 telomere translocation. The three brothers with the balanced translocation were father to one each of the three proband's cousins. All four affected girls showed a similar phenotype with pre/postnatal growth retardation, microcephaly, severe developmental delay/mental retardation, poor/absent speech, and a distinct pattern of malformation. On examination there were coarsening of facial features with low fronto-temporal hairline; thick eyebrows; bilateral epicanthal folds; hypertelorism; prominent nose with squared nasal root and narrow alar base; low-set posteriorly rotated large ears with a prominent anthelix; high arched palate; prominent chin; hands/feet brachydactyly; bilateral squint; hypotonia; and muscle hypotrophy. A slow overall improvement was seen in all patients over time. To our knowledge, this complex subtelomeric rearrangement in our patients has never been reported so far. Monosomy 10q has recently been described either isolated or as part of a complex rearrangement involving telomeres other than the 3q. Trisomy 3q29 has not yet been reported, but our patients resembled cases with 3q26 trisomy suggesting that the critical region of duplication for this phenotype is in 3q29.

Molecular and clinical characterization of de novo and familial cases with microduplication 3q29: guidelines for copy number variation case reporting

“…The phenotype has been said to partially overlap that of Brachmann de Lange/Cornelia de Lange syndrome (OMIM#122470). Many groups have described the cytogenetic critical region associated with the 3q duplication syndrome as involving 3q26 (Aqua et al ., 1995;Rizzu et al ., 1997;Faas et al ., 2002); however Battaglia et al (2006) suggested that it was 3q29. The four index patients which we have presented do not have a phenotype consistent with Brachman de Lange syndrome, suggesting that 3q29 is unlikely to be involved in the previously described 'Duplication 3q syndrome'.…”

“Essentially” pure trisomy 3q27 → qter: Further delineation of the partial trisomy 3q phenotype

“…The critical genomic region for most of the clinical features described was recently narrowed down to 3q26.3 ! 3q29 [Faas et al, 2002;Battaglia et al, 2006]. Cases with more distal duplications-either sole abnormalities or associated with a deletion of an other chromosomal segment-have been rarely described.…”

A girl with a 14.7 Mb 3q26.32–q28 duplication: a new report of 3q duplication syndrome and a literature review

“…The critical genomic regions for most of the clinical features were proposed between 3q26.31 and 3q27.3 by Aqua et al (1995) and Faas et al (2002). In contrast, Battaglia et al (2006) suggested that the region was at 3q29.…”