An 8.35 Mb overlapping interstitial deletion of 8q24 in two patients with coloboma, congenital heart defect, limb abnormalities, psychomotor retardation and convulsions

Verheij, Joanne; Munnik, Sonja A de; Dijkhuizen, Trijntje; Leeuw, Nicole de; Weghuis, Daniël Olde; Hoek, G.; Rijlaarsdam, R. S.; Thomasse, Y. E. M.; Dikkers, Frederik G.; Marcelis, Carlo; Ravenswaaij-Arts, van Conny

doi:10.1016/j.ejmg.2009.05.006

Cited by 59 publications

(75 citation statements)

References 13 publications

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“…8 Other variable clinical features such as severe feeding difficulties (3/6), bilateral optic nerve hypoplasia (2/6) and branchial arch defects (2/6), the latter having been described in 3/7 8q24 deletion patients, were also observed in these patients. [6][7][8] Taken together, these observations emphasize the major role of PUF60 in the phenotype of Verheij syndrome and contribute to the phenotypical delineation of this condition.…”

Section: Discussionsupporting

confidence: 53%

“…Indeed, all six patients (present study and patient 6 from the study of Dauber et al 8 ) carrying a PUF60 variant have the same core facial gestalt (Figure 1 and Table 1). [6][7][8] The other overlapping clinical features were DD (6/6), cardiac defect (5/6), short stature (5/6), vertebral anomalies (3/6), moderate distal limb anomalies (5/6) and joint laxity/dislocation (5/6), suggesting that PUF60 variants that affect function are likely to be associated with this part of the phenotype observed in these patients (Table 1), namely the developmental, craniofacial, skeletal and cardiac phenotype. These findings are consistent with the significant and reproducible reduction of body length observed in the puf60 morphants by Dauber et al, 8 and the demonstration that PUF60 loss of function drove a cardiac defect phenotype in 34% of puf60 MO-injected zebra fish embryos (Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…This rare condition, also named Verheij syndrome, is characterized by low birth weight and growth retardation, microcephaly, vertebral anomalies, joint laxity, and/or dislocation, developmental delay (DD), cardiac defects, renal defects and dysmorphic features. 6,7 It can be considered, at least for now, as a contiguous gene syndrome characterized by the existence of apparently unrelated clinical features in the same patient, resulting from a chromosomal rearrangement involving contiguous dosage-sensitive genes. Indeed, in 1 FHU TRANSLAD, Centre de Référence Maladies Rares ˂˂ Anomalies du développement et syndromes malformatifs ˃˃ de l'Est, Centre de Génétique, CHU de Dijon, Dijon, France; 2013, Dauber et al 8 reported on five individuals carrying overlapping 8q24.3 microdeletions that included SCRIB, NRBP2 and PUF60, and demonstrated by using functional experiments on zebrafish that the patients' phenotype resulted from a combination of endophenotypes induced by the haploinsufficiency of PUF60 (short stature, craniofacial and cardiac anomalies) and SCRIB (coloboma and renal anomalies).…”

Section: Introductionmentioning

confidence: 99%

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Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature

et al. 2016

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International audienceVerheij syndrome, also called 8q24.3 microdeletion syndrome, is a rare condition characterized by ante- and postnatal growth retardation, microcephaly, vertebral anomalies, joint laxity/dislocation, developmental delay (DD), cardiac and renal defects and dysmorphic features. Recently, PUF60 (Poly-U Binding Splicing Factor 60 kDa), which encodes a component of the spliceosome, has been discussed as the best candidate gene for the Verheij syndrome phenotype, regarding the cardiac and short stature phenotype. To date, only one patient has been reported with a de novo variant in PUF60 that probably affects function (c.505C>T leading to p.(His169Tyr)) associated with DD, microcephaly, craniofacial and cardiac defects. Additional patients were required to confirm the pathogenesis of this association and further delineate the clinical spectrum. Here we report five patients with de novo heterozygous variants in PUF60 identified using whole exome sequencing. Variants included a splice-site variant (c.24+1G>C), a frameshift variant (p.(Ile136Thrfs*31)), two nonsense variants (p.(Arg448*) and p.(Lys301*)) and a missense change (p.(Val483Ala)). All six patients with a PUF60 variant (the five patients of the present study and the unique reported patient) have the same core facial gestalt as 8q24.3 microdeletions patients, associated with DD. Other findings include feeding difficulties (3/6), cardiac defects (5/6), short stature (5/6), joint laxity and/or dislocation (5/6), vertebral anomalies (3/6), bilateral microphthalmia and irido-retinal coloboma (1/6), bilateral optic nerve hypoplasia (2/6), renal anomalies (2/6) and branchial arch defects (2/6). These results confirm that PUF60 is a major driver for the developmental, craniofacial, skeletal and cardiac phenotypes associated with the 8q24.3 microdeletio

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature

et al. 2016

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“…They suggested that other genes which are present in the deleted region may be responsible for these additional features. 8 Our patient showed the typical facial features and skeletal signs of TRPSII. The clinical findings are strongly associated with TRPSII, 8q24.1 deletion syndrome.…”

Section: Discussionsupporting

confidence: 53%

“…3 Verheij et al, reported two patients with a deletion in the long arm of chromosome 8. 8 In one of them the deletion region (q24.1-24.3) included the TRPS1 and EXT1 genes. The patient had the facial features of TRPSII, however, he had hand anomalies including the fusion of the third and fourth metatarsals and oligodactily, a unilateral coloboma of the right iris, pulmonary stenosis, ventricular septal defects.…”

Section: Discussionmentioning

confidence: 99%

Trichorhinophalangeal syndrome type II presenting with short stature in a child

Hazan

Korkmaz

Yararbaş³

et al. 2016

Arch Argent Pediat

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Trichorhinophalangeal syndrome type II (TRPSII) (synonym: Langer-Giedon syndrome) is a rare autosomal dominant contiguous gene syndrome, resulting from a microdeletion encompassing the EXT1 and the TRPS1 gene at 8q24 (MIM#150230). This syndrome combines the clinical features of two autosomal dominant disorders, trichorhinophalangeal syndrome type I (MIM#190350) and hereditary multiple osteochondromas type I (MIM # 133700). TRPSII is characterized by sparse scalp hair, a long nose with a bulbous tip, long flat philtrum, cone-shaped epiphyses of the phalanges, retarded bone age in infancy and multiple cartilaginous osteochondromas. We report a Turkish patient who had the clinical features and skeletal signs of TRPSII in whom a 13.8Mb deletion in 8q23.1-8q24.13 was detected.

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Long‐term follow‐up of four patients with langer–giedion syndrome: Clinical course and complications

Schinzel

Riegel

Baumer

et al. 2013

American J of Med Genetics Pt A

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Long-term observations of individuals with the so-called Langer-Giedion (LGS) or tricho-rhino-phalangeal type II (TRPS2) are scarce. We report here a on follow-up of four LGS individuals, including one first described by Andres Giedion in 1969, and review the sparse publications on adults with this syndrome which comprises ectodermal dysplasia, multiple cone-shaped epiphyses prior to puberty, multiple cartilaginous exostoses, and mostly mild intellectual impairment. LGS is caused by deletion of the chromosomal segment 8q24.11-q24.13 containing among others the genes EXT1 and TRPS1. Most patients with TRPS2 are only borderline or mildly cognitively delayed, and few are of normal intelligence. Their practical skills are better than their intellectual capability, and, for this reason and because of their low self-esteem, they are often underestimated. Some patients develop seizures at variable age. Osteomas on processes of cervical vertebrae may cause pressure on cervical nerves or dissection of cerebral arteries. Joint stiffness is observed during childhood and changes later to joint laxity causing instability and proneness to trauma. Perthes disease is not rare. Almost all males become bald at or soon after puberty, and some develop (pseudo) gynecomastia. Growth hormone deficiency was found in a few patients, TSH deficiency so far only in one. Puberty and fertility are diminished, and no instance of transmission of the deletion from a non-mosaic parent to a child has been observed so far. Several affected females had vaginal atresia with consequent hydrometrocolpos.

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An 8.35 Mb overlapping interstitial deletion of 8q24 in two patients with coloboma, congenital heart defect, limb abnormalities, psychomotor retardation and convulsions

Cited by 59 publications

References 13 publications

Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature

Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature

Trichorhinophalangeal syndrome type II presenting with short stature in a child

Long‐term follow‐up of four patients with langer–giedion syndrome: Clinical course and complications

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