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Overgrowth syndromes (OGS) comprise a heterogeneous group of disorders whose main characteristic is that the weight, height or the head circumference are above the 97th centile or 2-3 standard deviations above the mean for age, gender, and ethnic group. Several copy-number variants (CNVs) have been associated with the development of OGS, such as the 5q35 microdeletion or the duplication of the 15q26.1-qter, among many others. In this study, we have applied 850K SNP-arrays to 112 patients and relatives with OGS from the Spanish OverGrowth Registry Initiative. We have identified CNVs associated with the disorder in nine individuals (8%). Subsequently, whole genome sequencing (WGS) analysis was performed in these nine samples in order to better understand these genomic imbalances. All the CNVs were detected by both techniques, settling that WGS is a useful tool for CNV detection. We have found six patients with genomic abnormalities associated with previously well-established disorders and three patients with CNVs of unknown significance, which may be related to OGS, based on scientific literature. In this report, we describe these findings and comment on genes associated with OGS that are located within the CNV regions., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

SETD2 belongs to the family of histone methyltransferase proteins and has been associated with three nosologically distinct entities with different clinical and molecular features: Luscan-Lumish syndrome (LLS), intellectual developmental disorder, autosomal dominant 70 (MRD70), and Rabin-Pappas syndrome (RAPAS). LLS [MIM #616831] is an overgrowth disorder with multisystem involvement including intellectual disability, speech delay, autism spectrum disorder (ASD), macrocephaly, tall stature, and motor delay. RAPAS [MIM #6201551] is a recently reported multisystemic disorder characterized by severely impaired global and intellectual development, hypotonia, feeding difficulties with failure to thrive, microcephaly, and dysmorphic facial features. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and potentially endocrine. Three patients who carried the missense variant p.Arg1740Gln in SETD2 were reported with a moderately impaired intellectual disability, speech difficulties, and behavioral abnormalities. More variable findings included hypotonia and dysmorphic features. Due to the differences with the two previous phenotypes, this association was then named intellectual developmental disorder, autosomal dominant 70 [MIM 620157]. These three disorders seem to be allelic and are caused either by loss-of-function, gain-of-function, or missense variants in the SETD2 gene. Here we describe 18 new patients with variants in SETD2 , most of them with the LLS phenotype, and reviewed 33 additional patients with variants in SETD2 that have been previously reported in the scientific literature. This article offers an expansion of the number of reported individuals with LLS and highlights the clinical features and the similarities and differences among the three phenotypes associated with SETD2 .

Beckwith-Wiedemann syndrome spectrum (BWSp) is an overgrowth disorder caused by imprinting or genetic alterations at the 11p15.5 locus. Clinical features include overgrowth, macroglossia, neonatal hypoglycaemia, omphalocele, hemihyperplasia, cleft palate, and increased neoplasm incidence. The most common molecular defect observed is hypomethylation at the imprinting centre 2 (KCNQ1OT1:TSS DMR) in the maternal allele, which accounts for approximately 60% of cases, although CDKN1C pathogenic variants have been reported in 5-10% of patients, with a higher incidence in familial cases. In this study, we examined the clinical and molecular features of all cases of BWSp identified by the Spanish Overgrowth Registry Initiative with pathogenic or likely pathogenic CDKN1C variants, ascertained by Sanger sequencing or next-generation sequencing, with special focus on the neoplasm incidence, given that there is scarce knowledge of this feature in CDKN1C -associated BWSp. In total, we evaluated 21 cases of BWSp with CDKN1C variants; 19 were classified as classical BWS according to the BWSp scoring classification by Brioude et al. One of our patients developed a mediastinal ganglioneuroma. Our study adds evidence that tumour development in patients with BWSp and CDKN1C variants is infrequent, but it is extremely relevant to the patient's follow-up and supports the high heterogeneity of BWSp clinical features associated with CDKN1C variants.