SWI/SNF-Related SMARCA2 Gene Mutation Associated with Nicolaides–Baraitser's Syndrome: Follow-up Study

Abstract

Nicolaides–Baraitser's syndrome is a rare, dominantly inherited well-delineated syndrome caused by mutations in the SMARCA2 gene which is located on the small arm of chromosome 9. In this study, a de novo missense variant, which was identified in a 3-year-old boy by whole exome sequencing is reported. The de novo heterozygous V1198M missense variant in SMARCA2 gene in exon 25 is novel. Identifying the condition is crucial for the long-term management and family counseling. Follow-up over 4 years revealed improvements in overall performance.

Introduction

Nicolaides–Baraitser's syndrome (NCBRS, OMIM # 601358) is the most clinically and molecularly recognizable phenotype within the SWItch/sucrose nonfermentable (SWI/SNF)-related intellectual disability disorders (SSRIDDs). NCBRS is dominantly inherited; however, de novo variants can occur during the formation of reproductive cells or in early embryonic development. All known cases of NCBRS have been sporadic. The cardinal features of NCBRS are defined as intellectual disability (ID), short stature, microcephaly, typical face, sparse hair, brachydactyly, prominent interphalangeal joints, behavioral problems, and seizures. ^{1 2}

The facial features are not generally apparent in the newborn period and early childhood; however, coarsening of the face and increased skin wrinkling occur over time. Van Houdt et al reported mutations in SMARCA2 gene in patients with NCBRS ³ and confirmed by Wolff et al. ⁴ The SMARCA2 gene is one of the SMARC genes that is involved in SSRIDD. Diagnosis is established by identifying a heterozygous SMARCA2 pathogenic variant by molecular genetic testing. SMARCA2 gene has 34 exons that encode nine conserved domains. SMARCA2 performs adenosine triphosphate (ATP) hydrolysis, binds acetylated histones, regulates transcription, and acts as a tumor suppressor gene. SMARCA2 and SMARCA4 are the two mutually exclusive ATPase subunits of the SWI/SNF complex that share high homology and cause distinct phenotypes within the disease spectrum (NCBRS vs. Coffin–Siris' syndrome).

Although the clinical phenotype is well delineated, only100 cases are reported to date. The first case of NCBRS with a novel mutation from India is reported in this article based on the clinical phenotype and genetic evaluation. Further follow-up of the patient and development is reported.

Case History

The patient was a 5-year-old male child born to nonconsanguineous parents at 40 weeks of gestation. The birth weight was 2.9 kg. The child had both motor and cognitive impairments and walked at 3 years of age. He developed seizures at 18 months of age for which antiepileptic drugs were given. Electroencephalogram was abnormal with generalized seizure activity. Magnetic resonance image of the brain was normal. Karyotype was normal (46XY). Genetic analysis for fragile X syndrome was negative. He was referred for genetic workup at 5 years of age as the parents were planning for the next pregnancy. Clinically, the child was very aggressive and hyperactive. He was totally nonverbal and had a short stature (<third centile) with microcephaly. The facial features were coarse with a triangular face and malar hypoplasia, thin upper lip, and a thick everted lower lip with long philtrum. He had long eyelashes, relatively large ears, scalp hair was sparse, wrinkles were present over the abdomen ( Fig. 1A , 1B ), and cryptorchidism was noted. A chromosomal microarray (Illumina Human CytoSNP-12) revealed a small segment of regions of homozygosity on chromosome 4. Whole exome sequencing was performed for a definite diagnosis.

Fig. 1.

( A ) Child showing sparse hair. ( B ) Abdominal skin wrinkling.

Results

The clinical phenotype is described in Table 1 . Whole exome sequencing identified three heterozygous missense variants on chromosome 9, 12, and 1 in the index patient. A heterozygous missense variant in exon 25 of the SMARCA2 gene on chromosome 9 with the amino acid substitution of methionine for valine at codon 1198 (p.V1198M) was detected ( Fig. 2 ). The V1198M variant was not present in both 1000 Genomes and ExAC databases, and it was predicted to be damaging by SIFT, PolyPhen, LRT, and MutationTaster. The variant was confirmed by Sanger sequence. Variants in the KMT2D gene in exon 2 and the CAMTA1 in exon 9 in the index patient were found to be benign. Sanger sequencing of the parents revealed absent SMARCA2 mutation in both the parents. The heterozygous KMT2D variant was detected in the unaffected father and not in the mother, the heterozygous CAMTA1 variant was detected in the unaffected mother and not in the father indicating that both KMT2D and CAMTA1 were unlikely to be the causative genes associated with the phenotype of the index patient.

Table 1. Most common clinical findings in 61 reported individuals with Nicolaides–Baraitser's syndrome and in the present case.

Finding	% of affected individuals	Present case
Intellectual disability	100%	++
Sparse hair	97%	+
Prominent interphalangeal joints	85%	No
Coarse facies	77%	Yes
Microcephaly	65%	Yes
Seizures	64%	++

Source: From Sousa et al (2014).

Fig. 2.

SMARCA2 gene with the amino acid substitution of methionine for valine at codon 1198 (p.V1198M; D).

Discussion

This was the first clinically and molecularly diagnosed NCBRS from India with a 4-year follow-up and adds to the existing small number of cases reported as well as an addition of a new variant in SMARCA2 gene. Prior to this, one clinically diagnosed case without mutation analysis is reported from India. ⁵ The classical facial features with absent speech, sparse hair, seizures with severe behavioral changes, and ID observed in our patient correlated well with NCBRS. The novel de novo missense mutation p.V1198M identified in our patient lies in the Hel-C terminal encompassing the exon 25 located very close to p. Ala1201 and p.Gly1202Cys reported by Van Houdt et al. In a study of 44 individuals, 36 exonic mutations were reported. Exon 25 and exon 18 were the most common sites involved in SMARCA2 gene. Comparing the genotype–phenotype as reported by Sousa and Heinemann, pathogenic variants in exon 25 of domain VI are associated with severe ID and seizures. Missense pathogenic variants affecting arginine at position 1159 are reported to be associated with severe ID. Mari et al reported the association of p.Ala1156 in domain VI with absent speech and ID. The p.V1198M mutation found in our patient fits into the phenotype described by Mari et al. ⁶ Overall, the study adds important new information to the genetic causes of NCBRS. There may be some genotype–phenotype correlations (Sousa et al, 2014) (mutations at domain VI with severe ID and seizures; mutations affecting residues Pro883, Leu946, and Ala1201 with mild phenotypes), but the numbers are still too small to draw any definitive conclusions.

Chater-Diehl et al generated a DNA methylation (DNAm) signature associated with NCBRS by comparing patient samples with pathogenic variants in the SMARCA2 gene and facilitated classifying variant of uncertain significance (VUS) in SMARCA2 as “pathogenic” or “benign.” ^{7 8} They found that the DNAm model classifications of VUS were concordant with the clinical phenotype. Variants within the SMARCA2 ATPase/helicase domain are classified as “pathogenic” and associated with the typical phenotype of NCBRS. Those variants which are proximal to the domain are not associated with the DNAm signature or NCBRS clinical features. A variant just distal to the ATPase/helicase domain is associated with a partial DNAm signature and a mild/atypical NCBRS clinical phenotype. In our patient, the novel variant is in the ATPase/helicase domain and presented with classical clinical features of NCBRS.

Molecular Pathogenesis

SMARCA2 is a subunit of the BRG1-associated factors complex, the human analog of the SWI/SNF complex and is essential for the regulation of gene expression. Pathogenic variants in SMARCA2 most likely cause a dominant-negative or gain-of-function effect and aberrant chromatin remodeling causing downstream dysregulation of further genes and resulting in the NCBRS phenotype. Identification of the novel variant in the present case needs to be studied further by modeling this variant V1198M in model organisms by CRISPR-Cas that would provide valuable functional information about the impact of this variant in animal development.

Impact on the Family and Follow-up

The major behavioral changes observed in these children include an aggressive behavior, temper tantrums, or autism with short attention span and cause extreme stress and anxiety in the family. In the reported patient, due to poor impulse control, hyperactivity, and no comprehension of danger, it is very tiring for the family members to manage the child. Feeding is difficult as the child needed special attention. Day-to-day management is very distressing for the family. A recent re-evaluation of the patient at 7 years of age revealed that with supportive therapies, remarkable improvement in behavior, hyperactivity, and speech (he now speaks a few words) can occur. He is attending a special school under the supervision of a special teacher. He is now toilet trained and started feeding himself with a spoon. Resham et al reported on a patient who was followed up until 20 years of age and who showed improvement in speech and intellectual development and attended the special stream in a local college. ⁹ Thus, the progression of the syndrome is clinically variable in development and the focus of management should be on behavioral modification and speech therapy which will have the greatest impact on the patient's family.

Genetic Counseling

The family is counseled with regard to the next pregnancy. Since the mutation observed in the patient is de novo, the recurrence will be negligible. The presence of other mutations, KMT2D gene in exon 2 and CAMTA1 in exon 9, is not significant as the KMT2D variant is detected in the unaffected father and not in the mother, and CAMTA1 variation is detected in the unaffected mother and not in the father indicating that KMT2D and CAMTAI are unlikely to be of clinical significance. The couple subsequently had another child who is unaffected.

Conclusion

In the present study, NCBRS with the classical clinical phenotype is reported and improvement was the clinical picture was noted on follow-up. The recurrence risk is low as the mutation is de novo. Although NCBRS is a well-delineated syndrome, it is markedly underdiagnosed. The detailed phenotype analysis helps in recognizing this syndrome.