A new case of de novo 19p13.2p13.12 deletion in a girl with overgrowth and severe developmental delay

Abstract

BackgroundWe report clinical and molecular cytogenetic characterization of a 2 year-old girl with 19p13.2p13.12 microdeletion and compare her clinical features with those of three other patients reported before.ResultArray comparative genomic hybridization (aCGH) revealed in the present patient a de novo microdeletion of 1.45 Mb within 19p13.2p13.12. The deletion includes seven OMIM genes: MAN2B1, RNASEH2A, KLF1, GCDH, NFIX, CACNA1A and CC2D1A.DiscussionThe present case and three other patients with partially overlapping 19p13 microdeletion share the following features: psychomotor and language delay, intellectual disability, seizures, hypotonia, skeletal anomalies and facial dysmorphism. The smallest region of overlapping between all four reported patients is around 300 kb and spans only two genes: NFIX and CACNA1A. Their haploinsufficincy could be the base for the phenotype -genotype correlation.

Further delineation of Malan syndrome

“…It is caused by heterozygous variants or deletions of the gene nuclear factor I X ( NFIX ; MIM# 164005 ) , located at chromosome 19p13.2 (Malan et al., 2010). Since the first description the entity has been described in 35 individuals, to date (Auvin, Holder‐Espinasse, Lamblin, & Andrieux, 2009; Bonaglia et al., 2010; Dolan et al., 2010; Dong et al., 2016; Gurrieri et al., 2015; Jezela‐Stanek et al., 2016; Jorge et al., 2015; Klaassens et al., 2015; Kuroda et al., ; Lu et al., 2017; Lysy et al., 2009; Martinez et al., 2015; Natiq et al., 2014; Nimmakayalu et al., 2013; Oshima et al., 2017; Priolo et al., 2012; Shimojima et al., 2015; Yoneda et al., 2012). Haploinsufficiency of NFIX has been proposed as leading causative mechanism in Malan syndrome (Gurrieri et al., 2015; Klaassens et al., 2015; Malan et al., 2010).…”

Malan syndrome (Sotos syndrome 2) in two patients with 19p13.2 deletion encompassing NFIX gene and novel NFIX sequence variant

“…Descriptions of patients presented so far in the literature comprise several cases of chromosomal aberrations in 19p13.2/19p13.13 band reported by Lysy et al 1 , Dolan et al 2 , Malan et al 3 , Bassuk et al 4 , Wangensteen et al 5 , Natiq et al 6 , Schwemmle et al 7 , Klaassens et al 8 , Shimojima et al 9 and point mutations in NFIX gene (localized within 19p13.2) reported by Malan et al 3 , Klaassens et al 8 , Priolo et al 10 , Yoneda et al 11 in patients with Sotos-like and Marshall-Smith (MRSHSS) syndromes. Unfortunately, due to the limited number of these cases, no definitive conclusions about the genotype-phenotype correlations can be made.…”

“…As patients with 19p13.2 and NFIX gene aberrations have been described in previous papers 2,3,6,8,10 , we will not present another detailed comparison. Instead our goal is to discuss physical features consistent with Sotos syndrome 2 (Malan syndrome) based on literature review and two new cases.…”

Malan syndrome in a patient with 19p13.2p13.12 deletion encompassing NFIX and CACNA1A genes: Case report and review of the literature

“…NFIX (OMIM * 164005), a member of the nuclear factor I family of transcription factors, is essential for normal brain and skeletal development and Nfix deficiency in mice leads to brain malformations including ventriculomegaly and partial agenesis of the corpus callosum (Driller et al, ; Malan et al, ). To date, together with the present study, 35 patients were described with Malan syndrome phenotype, all of them presenting deletions involving NFIX gene, with variable breakpoints (Auvin et al, ; Bonaglia et al, ; Dolan et al, ; Dong et al, ; Hino‐Fukuyo et al, ; Jezela‐Stanek et al, ; Jorge et al, ; Karmarkar et al, ; Klaassens et al, ; Kuroda et al, ; Lyon et al, ; Lysy et al, ; Malan et al, ; Natiq et al, ; Nimmakayalu et al, ; Priolo et al, ; Shimojima et al, ; Welham et al, ) (Figure ).…”