Molecular and clinical characterization of patients with overlapping 10p deletions

Abstract

Chromosome 10p terminal deletions have been associated with DiGeorge phenotype, and within the same genomic region haploinsufficiency of GATA3 causes the HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia). We have performed detailed molecular analysis of four patients with partial overlapping 10p deletions by using FISH-mapping, array-CGH, and custom-designed high-resolution oligonucleotide array. All four patients had mental retardation and speech impairment and three of them showed variable signs of HDR syndrome. In addition, two patients had autistic behaviors and had similar dysmorphic features giving them a striking physical resemblance. A review of the literature identified 10 previously published cases with similar 10p deletions and reliable molecular or molecular cytogenetic mapping data. The combined information of present and previous cases suggests that partial deletions of 10p14-p15 represent a syndrome with a distinct and more severe phenotype than previously assumed. The main characteristics include severe mental retardation, language impairment, autistic behavior, and characteristic clinical features. A critical region involved in mental retardation and speech impairment is defined within 1.6 Mb in 10p15.3. In addition, deletion of 4.3 Mb within 10p14 is associated with autism and characteristic clinical findings.

The origin and evolution of vertebrate sex chromosomes and dosage compensation

“…Moreover, the snake Z chromosome is known to share homology with human 3p21-p24, 7p14-p15, 10p11-p15 and 17q21-q24 (Matsubara et al, 2006). Monosomy of at least parts of these regions also survive to birth, albeit with phenotypes of varying severity (Wieczorek et al, 1997;Schwarzbraun et al, 2006;Barber, 2008;Puusepp et al, 2009;Lindstrand et al, 2010). This suggests that dosage imbalance from the autosome pair that became the chicken Z, and the autosome pair that became the snake Z, is somewhat tolerable in amniotes.…”

Duplication of the Miller-Dieker Critical Region in a Patient with a Subtelomeric Unbalanced Translocation t(10;17)(p15.3;p13.3)

“…In addition, our patient has severe visual dysfunction and immaturity of auditory brainstem-evoked responses, which might be associated with the reduction of the visual cortex found in the 17p13.3 duplication. However, visual and auditory dysfunctions are highly conserved among all patients with partial monosomy 10p [Bourrouillou et al, 1981;Fryns et al, 1981;Battaglia et al, 2007;Lindstrand et al, 2010].…”

“…Similarly, haploinsufficiency of the region 10p14 ] pter, distal to DGCR2, results in hypoparathyroidism, sensorineural deafness and renal anomaly, features that determine the HDR syndrome Fukami et al, 2011]. In this region, it has been described that the GATA3 gene, which is involved in the embryonic development of the parathyroids, auditory system and kidneys, plays a critical role in the development of different neural populations within the mammalian central nervous system Karunaratne et al, 2002;Lindstrand et al, 2010]. In the embryonic midbrain, GATA3 expression correlates with the development of the optic tectum [Kornhauser et al, 1994], while in the developing hindbrain, loss of GATA3 affects differentiation of the vestibuloacoustic efferent neurons and migration of the facial branchiomotor neurons [Pata et al, 1999].…”

“…Terminal deletions of chromosome 10p have been published on several occasions [Bourrouillou et al, 1981;Fryns et al, 1981;Suciu and Nanulescu, 1983;Kinoshita et al, 1992;Shapira et al, 1994;Schinzel, 2001;Roos et al, 2006;Battaglia et al, 2007;Lindstrand et al, 2010]; however, only 5 cases with a small deletion that affected the chromosome region 10p14 ] pter have been reported [Bourrouillou et al, 1981;Fryns et al, 1981;. In general, the majority of the pure deletions reported for chromosome 10p are associated with the DiGeorge-like phenotype (DGSII) or with the hypoparathyroidism-sensorineural deafness/renal syndrome (HDR), the latter associated with the GATA3 gene [Schuffenhauer et al, 1995;Dasoiuki et al, 1997;Van Esch et al, 2000;Fukami et al, 2011].…”

GATA3 (GATA binding protein 3)

“…Deletion of chromosome 10 (del10p) and GATA3 gene mutations leading to haploinsufficiency associated with HDR syndrome (Van Esch et al, 2000;Nesbit et al, 2004;Ali et al, 2007;Lindstrand et al, 2010).…”