ESPE2024 Poster Category 1 Late Breaking 2 (10 abstracts)
Heterozygous PLAG1 gene variants causing Silver-Russell syndrome in a case series of 4 patients
Alicia Juriaans 1 , Katherine Lachlan 1,2 , Jenny Carmichael 3 , Justin Davies 1,4 , Deborah Mackay 1 , Karen Temple 1,2 & Gabriella Gazdagh 1,2
1Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. 2Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Trust, Southampton, United Kingdom. 3East Anglian Medical Genetics Service, Addenbrooke´s Hospital, Cambridge, United Kingdom. 4Paediatric Endocrinology Department, University Hospital Southampton NHS Trust, Southampton, United Kingdom
Background: Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous syndrome, characterized by pre- and postnatal growth restriction among other features. Pathogenic variants in genes involved in the HMGA2-PLAG1-IGF2 pathway have been found to cause an SRS phenotype. Here we present four individuals with variants in the PLAG1 gene, exhibiting features of SRS. Two siblings of the same family inherited the PLAG1 variant from the father.
Methods: All patients who had presented to the Clinical Genetics department, underwent comprehensive genetic work-up. Further studies were performed to identify family members with the same variant.
Results: We present one case of a 157 kb deletion encompassing PLAG1 in an infant girl with pre- and postnatal growth restriction, several dysmorphic features and a unilateral cleft lip and palate. Three additional patients are described from the same family with a PLAG1 variant, exhibiting pre- and postnatal growth restriction, learning disability, and several dysmorphic features. None of the patients had body asymmetry or significant episodes of hypoglycaemia. Two of the four patients had a score of ≥4 on the Netchine-Harbisson Clinical Scoring System.
| Patient 1 | Patient 2 | Patient 3 | Patient 4 | |
| Defect | PLAG1 deletion arr[GRCh38] 8q12.1(56124370_56281604)x1] |
PLAG1 c.1310dup; p.(Ser439GlufsTer94) |
PLAG1 c.1310dup; p.(Ser439GlufsTer94) |
PLAG1 c.1310dup; p.(Ser439GlufsTer94) |
| Sex | Female | Male | Male | Male |
| Current age | 5 months | 5.5 years | 3.5 years | 51 years |
| Perinatal | ||||
| Gestational age | 37 weeks, 6 days | 38 weeks | 38 weeks | NK |
| IUGR | + | + | + | NK |
| Birth weight g/SDS | 2260/-1.87 | 2060/-2.56 | 2070/-2.53 | NK |
| Tube-feeding needed | - | + | + | NK |
| NH-CSS score | 2/6 | 5/6 | 5/6 | 1/4 |
| SGA (birth weight and/or birth length) | - | + | + | NK |
| Postnatal growth failure | + | + | + | + |
| Relative macrocephaly at birth | - | + | + | NK |
| Protruding forehead | + | + | + | - |
| Body asymmetry | - | - | - | - |
| Feeding difficulties and/or low BMI | - | + | + | - |
| Other features | Unilateral cleft lip Naevus flammeus (forehead) | Traits of ASD | Traits of ASD VUS POGZ | VUS POGZ |
| IUGR: intrauterine growth retardation; SDS: standard deviation score; NH-CSS: Netchine-Harbisson Clinical Scoring System; SGA: small for gestational age; GH: growth hormone; ASD: autism spectrum disorder; VUS: variant of uncertain significance; NK: not known. | ||||
Conclusion: Overall, while PLAG1 variants represent a relatively rare cause of SRS, they highlight the genetic heterogeneity of the condition and underscore the importance of comprehensive genetic testing, including whole exome/genome sequencing, in individuals with suspected (familial) SRS to identify underlying genetic aetiologies.
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