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Case Report: Novel pathogenic variant in NFIX in two sisters with Malan syndrome due to germline mosaicism.

ABSTRACT: Malan syndrome is an autosomal dominant disorder caused by pathogenic variants in NFIX with less than 100 cases reported thus far. NFIX is important for stem cell proliferation, quiescence, and differentiation during development and its protein plays a role in replication, signal transduction, and transcription. As a result of pathogenic variants, symptoms of Malan syndrome include overgrowth, intellectual disability, speech delay, and dysmorphic features. Currently, the recurrence risk for this disorder is indicated at less than 1%, standard for de novo autosomal dominant disorders. Herein, we report an additional set of sisters with the same novel pathogenic variant in NFIX and clinical features consistent with Malan syndrome providing evidence of germline mosaicism. Considering the rarity of this condition in conjunction with three previous reports of germline mosaicism, it is worthwhile to investigate and re-evaluate the proper recurrence risk for this condition. This discovery would be paramount for family planning and genetic counseling practices in families with affected individuals.

SUBMITTER: Langley E

PROVIDER: S-EPMC9682143 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Case Report: Novel pathogenic variant in NFIX in two sisters with Malan syndrome due to germline mosaicism.

Langley Elizabeth E Farach Laura S LS Mowrey Kate K

Frontiers in genetics 20221109

Malan syndrome is an autosomal dominant disorder caused by pathogenic variants in NFIX with less than 100 cases reported thus far. NFIX is important for stem cell proliferation, quiescence, and differentiation during development and its protein plays a role in replication, signal transduction, and transcription. As a result of pathogenic variants, symptoms of Malan syndrome include overgrowth, intellectual disability, speech delay, and dysmorphic features. Currently, the recurrence ...[more]

PMID: 36437934

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Project description:BackgroundMonosomy 1p36 is the most common terminal deletion syndrome with an autosomal dominant pattern of inheritance. This syndrome is defined by an extremely wide spectrum of characteristics; however, developmental delay and intellectual disability of various degree are present in all patients and about the 90% of patients have a severe intellectual disability. Dental agenesis or other dental anomalies have not been described in previous reports.Case presentationWe report the case of two little sisters born from healthy and non-consanguineous parents, presenting with dental anomalies and one of them with epilepsy, dilated cardiomyopathy with left-ventricular non-compaction, strabismus, history of poor growth, hypotonia and mild language delay. Patients were evaluated in several departments (genetic, child neuropsychiatric, cardiology, odontostomatology, ophthalmology, otorhinolaryngology) of Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy. They underwent investigations such as electrocardiogram, echocardiogram, dental orthopantomography X-Ray and Computed Tomography, electroencephalograms, abdomen ultrasound, blood tests, IQ tests, genetic analysis. They both have an Intelligence Quotient greater than 70 and a negative neurologic exam. Each sister carries the same 1p36 deletion of about 2.3 Mb. Genetic analysis of the parents' blood samples (Single Nucleotide Polymorphism- array, karyotype and Fluorescent In Situ Hybridization) did not reveal any deletion, translocation or inversion and confirmed the paternity. A third sib of the probands does not carry the 1p36 deletion or other quantitative alterations.ConclusionThis report describes a new trait linked to monosomy 1p36, namely a mild intellectual outcome associated with significant dental anomalies. Our finding suggests that 1p36 deletion syndrome may present with a mild cognitive impairment or even with a normal intellectual development: this is very important for the genetic counselling, especially in a prenatal setting. Moreover, we report the third study with recurrent 1p36 deletion syndrome in two siblings, likely due to germline mosaicism. Finally, we believe that the dental anomalies should be investigated in 1p36 deletion syndrome and that the spectrum of the condition could be broader than we assume.

Dataset Information

Case Report: Novel pathogenic variant in NFIX in two sisters with Malan syndrome due to germline mosaicism.

Publications

Case Report: Novel pathogenic variant in <i>NFIX</i> in two sisters with Malan syndrome due to germline mosaicism.

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