An Indian infant with de novo duplication of 16p chromosome: A rare genetic syndrome

Facial dysmorphism along with multiple congenital anomalies is observed in many genetic syndromes mostly in chromosomal microdeletion or duplication, which cannot be detected by conventional karyotype. Here, we report a case with facial dysmorphism, cleft palate, congenital heart defect, and umbilical hernia, diagnosed with duplication at chromosome 16p13.3 by array comparative genomic hybridization (CGH) at very early age. Array CGH is the advanced diagnostic technology; enable to diagnose chromosomal abnormalities earlier thus can provide appropriate medical management and prognostication.

Clinical and pathologic phenotype of a large family with heterozygous STUB1 mutation

ObjectiveTo describe the clinical and pathologic features of a novel pedigree with heterozygous STUB1 mutation causing SCA48.MethodsWe report a large pedigree of Dutch decent. Clinical and pathologic data were reviewed, and genetic analyses (whole-exome sequencing, whole-genome sequencing, and linkage analysis) were performed on multiple family members.ResultsPatients presented with adult-onset gait disturbance (ataxia or parkinsonism), combined with prominent cognitive decline and behavioral changes. Whole-exome sequencing identified a novel heterozygous frameshift variant c.731_732delGC (p.C244Yfs*24) in STUB1 segregating with the disease. This variant was present in a linkage peak on chromosome 16p13.3. Neuropathologic examination of 3 cases revealed a consistent pattern of ubiquitin/p62-positive neuronal inclusions in the cerebellum, neocortex, and brainstem. In addition, tau pathology was present in 1 case.ConclusionsThis study confirms previous findings of heterozygous STUB1 mutations as the cause of SCA48 and highlights its prominent cognitive involvement, besides cerebellar ataxia and movement disorders as cardinal features. The presence of intranuclear inclusions is a pathologic hallmark of the disease. Future studies will provide more insight into its pathologic heterogeneity.

Chromosome 16p13.3 Contiguous Gene Deletion Syndrome including the SLX4, DNASE1, TRAP1, and CREBBP Genes Presenting as a Relatively Mild Rubinstein–Taybi Syndrome Phenotype: A Case Report of a Saudi Boy

The classic Rubinstein–Taybi syndrome Type 1 (RSTS1, OMIM 180849) is caused by heterozygous mutations or deletions of the CREBBP gene. Herein, we describe the case of a Saudi boy with chromosome 16p13.3 contiguous gene deletion syndrome (OMIM 610543) including the SLX4, DNASE1, TRAP1, and CREBBP genes, but presenting with a relatively mild RSTS1 syndrome phenotype. Compared with previously reported cases with severe phenotypes associated with 16p13.3 contiguous gene deletions, our patient had partial deletion of the CREBBP gene (with a preserved 5′ region), which might explain his relatively mild phenotype.

A rare case of Rubinstein-Taybi Syndrome and gynecological malignancy

Rubinstein-Taybi syndrome (RSTS) is a congenital syndrome most associated with mutations on chromosome 16p13.3 that can result in both benign and malignant neurologic and hematologic neoplasms of various primary origins. We present the case of a 39-year old female with RSTS who presented with severe abdominal and pelvic pain. Abdominal and pelvic imaging revealed multiple masses involving the uterus, liver and spleen concerning for malignancy. Biopsies from the endometrium and cervix confirmed this as a poorly differentiated, widely invasive squamous cell carcinoma. This represents the first case of primary squamous cell carcinoma of gynecologic origin in a patient with Rubinstein-Taybi syndrome. This case aims to raise awareness of the gynecological malignancy in patients with RSTS as well as serves as a reminder to clinicians to have a broad differential diagnosis in all patients which may help lead to early recognition of pathology.

Heterozygous STUB1 mutation causes familial ataxia with cognitive affective syndrome (SCA48)

ObjectiveTo describe a new spinocerebellar ataxia (SCA48) characterized by early cerebellar cognitive-affective syndrome (CCAS) and late-onset SCA.MethodsThis is a descriptive study of a family that has been followed for more than a decade with periodic neurologic and neuropsychological examinations, MRI, brain SPECT perfusion, and genetic analysis. Whole exome sequencing was performed in 3 affected and 1 unaffected family member and subsequently validated by linkage analysis of chromosome 16p13.3.ResultsSix patients fully developed cognitive-affective and complete motor cerebellar syndrome associated with vermian and hemispheric cerebellar atrophy, suggesting a continuum from a dysexecutive syndrome slowly evolving to a complete and severe CCAS with late truncal ataxia. Three presymptomatic patients showed focal cerebellar atrophy in the vermian, paravermian, and the medial part of cerebellar lobes VI and VII, suggesting that cerebellar atrophy preceded the ataxia, and that the neurodegeneration begins in cerebellar areas related to cognition and emotion, spreading later to the whole cerebellum. Among the candidate variants, only the frameshift heterozygous c.823_824delCT STUB1 (p.L275Dfs*16) pathogenic variant cosegregated with the disease. The p.L275Dfs*16 heterozygous STUB1 pathogenic variant leads to neurodegeneration and atrophy in cognition- and emotion-related cerebellar areas and reinforces the importance of STUB1 in maintaining cognitive cerebellar function.ConclusionsWe report a heterozygous STUB1 pathogenic genetic variant causing dominant cerebellar ataxia. Since recessive mutations in STUB1 gene have been previously associated with SCAR16, these findings suggest a previously undescribed SCA locus (SCA48; MIM# 618093).