Introduction The Nuclear Factor I X (NFIX) gene encodes a transcription factor associated with Malan syndrome (MS) and Marshall-Smith syndrome (MSS). MS-associated NFIX microdeletions or NFIX intragenic variants, primarily clustered in exon 2, show no significant genotype–phenotype correlations among the individuals except higher frequency of epilepsy and EEG abnormalities in NFIX microdeletions cases. In contrast, MSS-associated NFIX variants are distributed across exons 6–10, with recurrent intragenic deletions involving exons 6 and 7. Clinical findings We report a male child who presented with global developmental delay with intellectual disability and stranger anxiety. His craniofacial features included a long, narrow triangular face, midfacial hypoplasia, broad forehead, deep-set eyes, blue sclera, and thick everted lips. Additionally, the patient exhibited pectus excavatum, scoliosis, and lumbar lordosis. Neurological and systemic examinations were unremarkable. The proband’s non-consanguineous parents and his elder brother showed no phenotypic similarity with the proband. A unique finding in this case was the equal length of the great toe and the adjacent two toes, a previously unreported feature in MS. Genetic analysis and novel findings Whole exome sequencing (WES) identified a novel heterozygous de novo single-base deletion in exon 6 of the NFIX gene (NM_001365902.3):p.(Thr275Profs*49), leading to a frameshift that introduces a premature stop codon after 49 incorrect amino acids, likely subjecting the transcript to degradation via nonsense-mediated decay. Notably, our proband exhibited phenotypic variability as compared with the commonly described MS phenotype. His birth weight, length, and occipitofrontal circumference were all below the 3rd percentile, which deviates from the MS phenotype. Furthermore, macrocephaly, prominent chin, down-slanting palpebral fissures, short nose, anteverted nares, hypotonia, and advanced bone age were absent. Conclusion Our proband had anthropometric measurements below the 3rd percentile along with phenotypic heterogeneity within MS and introduced a novel foot anomaly. A reassessment of the previously reported cases could provide deeper insights into the genetic and developmental mechanisms contributing to these distinct features.

Novel NFIX gene variant in Malan Syndrome

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2025年8月5日

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Shagufta Shaikh,
Sangeeta Sawant,
Susan Cherian,
Suresh K. G. Shettigar

摘要

Introduction

The Nuclear Factor I X (NFIX) gene encodes a transcription factor associated with Malan syndrome (MS) and Marshall-Smith syndrome (MSS). MS-associated NFIX microdeletions or NFIX intragenic variants, primarily clustered in exon 2, show no significant genotype–phenotype correlations among the individuals except higher frequency of epilepsy and EEG abnormalities in NFIX microdeletions cases. In contrast, MSS-associated NFIX variants are distributed across exons 6–10, with recurrent intragenic deletions involving exons 6 and 7.

Clinical findings

We report a male child who presented with global developmental delay with intellectual disability and stranger anxiety. His craniofacial features included a long, narrow triangular face, midfacial hypoplasia, broad forehead, deep-set eyes, blue sclera, and thick everted lips. Additionally, the patient exhibited pectus excavatum, scoliosis, and lumbar lordosis. Neurological and systemic examinations were unremarkable. The proband’s non-consanguineous parents and his elder brother showed no phenotypic similarity with the proband. A unique finding in this case was the equal length of the great toe and the adjacent two toes, a previously unreported feature in MS.

Genetic analysis and novel findings

Whole exome sequencing (WES) identified a novel heterozygous de novo single-base deletion in exon 6 of the NFIX gene (NM_001365902.3):p.(Thr275Profs*49), leading to a frameshift that introduces a premature stop codon after 49 incorrect amino acids, likely subjecting the transcript to degradation via nonsense-mediated decay.

Notably, our proband exhibited phenotypic variability as compared with the commonly described MS phenotype. His birth weight, length, and occipitofrontal circumference were all below the 3rd percentile, which deviates from the MS phenotype. Furthermore, macrocephaly, prominent chin, down-slanting palpebral fissures, short nose, anteverted nares, hypotonia, and advanced bone age were absent.

Conclusion

Our proband had anthropometric measurements below the 3rd percentile along with phenotypic heterogeneity within MS and introduced a novel foot anomaly. A reassessment of the previously reported cases could provide deeper insights into the genetic and developmental mechanisms contributing to these distinct features.