CANPMR syndrome and chromosome 1p32-p31 deletion syndrome coexist in two related individuals affected by simultaneous haplo-insufficiency of CAMTA1 and NFIA genes

Abstract

BackgroundNon-progressive cerebellar ataxia with mental retardation (CANPMR, OMIM 614756) and chromosome 1p32-p31 deletion syndrome (OMIM 613735) are two very rare inherited disorders, which are caused by mono-allelic deficiency (haplo-insufficiency) of calmodulin-binding transcription activator 1 (CAMTA1) and, respectively, nuclear factor 1 A (NFIA) genes. The yet reported patients affected by mono-allelic CAMTA1 dysfunction presented with neonatal hypotonia, delayed and ataxic gait, cerebellar atrophy, psychological delay and speech impairment, while individuals carrying a disrupted NFIA allele suffered from agenesis/hypoplasia of the corpus callosum, ventriculomegaly, developmental delay and urinary tract abnormalities. Both disorders were not seen in one patient together before.ResultsIn this study two related individuals affected by a complex clinical syndrome, characterized by cognitive, neurological and nephrological features were studied for the underlying genetic disorder(s) by molecular cytogenetics. The two individuals present dysmorphic facies, macrocephaly, generalized ataxia, mild tremor, strabismus, mild mental retardation and kidney hypoplasia. Moreover, neuro-radiological studies showed hypoplasia of corpus callosum. Genetic investigations revealed a paracentric inversion in the short arm of one chromosome 1 with breakpoints within CAMTA1 and NFIA coding sequences.ConclusionsTo the best of our knowledge, this is the first report of two patients harboring the simultaneous mono-allelic disruptions and consequent haplo-insufficiencies of two genes due to an inversion event. Disruption of CAMTA1 and NFIA genes led to neuro-psychological and nephrological dysfunctions, which comprised clinical features of CANPMR syndrome as well as chromosome 1p32-p31 deletion syndrome.

Loss‐of‐function variants in NFIA provide further support that NFIA is a critical gene in 1p32‐p31 deletion syndrome: A four patient series

“…The only clinical finding the three patients with the p.Arg69Ter nonsense variant share in common is macrocephaly, which further emphasizes the variable expressivity associated with NFIA haploinsufficiency. Intra‐familial variation in phenotype is also reported in families with intragenic gene deletions (Bayat et al, ; Coci et al, ; Nyboe et al, ) and microdeletions (Campbell et al, ; Lu et al, ). When comparing all patients in our cohort and patients with NFIA point mutations, intragenic deletions and disruptions, as well as chromosome 1p32‐p31 microdeletions, corpus callosum abnormalities are the most common findings reported.…”

“…Recently, Labonne et al () used comparative deletion mapping of all reported cases of 1p31.3p32.2 deletions, identifying NFIA as a gene in the minimal region of overlap and the gene likely responsible for intellectual disability and macrocephaly seen in individuals with this microdeletion. NFIA gene disruptions resulting from balanced translocations and intragenic deletions have also been reported with features consistent with the 1p32‐p31 deletion syndrome (Bayat, Kirchhoff, Madsen, Roos, & Kreiborg, ; Coci et al, ; Lu et al, ; Mikhail et al, ; Nyboe, Kreiborg, Kirchhoff, & Hove, ; Rao et al, ). A more detailed review of reported cases of 1p32‐p31 deletion syndrome, NFIA gene disruptions and intragenic deletions is available in the supplementary materials section.…”

Shared Neurodevelopmental Perturbations Can Lead to Intellectual Disability in Individuals with Distinct Rare Chromosome Duplications

“…Moreover, patients with duplicated regions that encompass the X-linked genes SOX3, STAG2, AIFM1, GRIA3, PAK3, and OCRL exhibit ID [ 22 , 23 , 24 , 25 , 26 , 56 , 57 , 58 ]. Moreover, six genes from the duplicated region 18p11.32-p11.21 are highly expressed in several regions of the CNS, from which three of them (LAMA1, MYOM1, and TGIF1) were duplicated in individuals with ID [ 18 , 19 , 20 ]. Furthermore, patients with duplication of 8q24.13q24.3 region involving the KCNQ3, PTK2, ASAP1, and NDRG1 genes, which are widely expressed in CNS, presented ID [ 14 , 16 , 53 ].…”

“…The 8q24.13q24.3 duplication identified is a rare chromosomal rearrangement associated with dysmorphic features, growth delay, and ID [ 13 , 14 , 15 , 16 ]. Moreover, variable levels of ID and cerebellum hypoplasia were described in patients with 18p11 duplications, however, few cases of pure duplications in this region have been reported with similar rearrangements so far [ 17 , 18 , 19 , 20 , 21 ]. Duplication at Xq22.3q27.2 is a condition with region enriched in genes related to neurological function involving many cases of ID, behavioral problems, holoprosencephaly, and cerebellar vermis hypoplasia [ 22 , 23 , 24 , 25 , 26 ].…”

Correction to: CANPMR syndrome and chromosome 1p32-p31 deletion syndrome coexist in two related individuals affected by simultaneous haplo-insufficiency of CAMTA1 and NFIA genes

“…Following publication of the original article [ 1 ], an error was identified in the article title: the gene name NFIA was incorrectly captured as NIFA . The article title has been updated above and in the original article.…”