Genetic Disorders in Prenatal Onset Syndromic Short Stature Identified by Exome Sequencing

Homma, Thaís Kataoka; Freire, Bruna L; Kawahira, Rachel Sayuri Honjo; Dauber, Andrew; Funari, Mariana Ferreira de Assis; Lerário, Antônio Marcondes; Nishi, Mirian Yumie; Albuquerque, Edoarda Vasco de Albuquerque; Vasques, Gabriela de Andrade; Collett‐Solberg, Paulo Ferrez; Sugayama, Sofia Mizuho Miura; Bertola, Débora Romeo; Kim, Chong; Arnhold, Ivo Jorge Prado; Malaquias, Alexsandra C.; Jorge, Alexander Augusto de Lima

doi:10.1016/j.jpeds.2019.08.024

Cited by 44 publications

(30 citation statements)

References 33 publications

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“…Due to syndromic short stature, hypertrichosis with long eyelashes and prominent eyebrows, WSS has phenotypic overlap with CdLS, Kabuki syndrome, Rubinstein‐Taybi syndrome, and Coffin‐Siris syndrome (Aoi et al, 2019; Bramswig et al, 2015; Homma et al, 2019; Negri et al, 2019). Homozygous LoF variants in TASP1 , which cleaves and activates KMT2A, should be considered in the differential diagnosis of WSS due to the overlapping phenotype of DD, hypotonia, microcephaly, feeding difficulties with failure‐to‐thrive, recurrent respiratory infections, cardiovascular malformations, happy demeanor, and distinctive facial features (Suleiman et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann‐Steiner syndrome

Sheppard

Campbell

Harr

et al. 2021

American J of Med Genetics Pt A

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Wiedemann‐Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype–phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty‐nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non‐LoF variants. This study identifies genotype–phenotype correlations as well as race‐facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long‐term outcomes in individuals with WSS.

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Section: Discussionmentioning

confidence: 99%

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann‐Steiner syndrome

Sheppard

Campbell

Harr

et al. 2021

American J of Med Genetics Pt A

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“…POC1A biallelic pathogenic variants are known to cause SOFT (Short stature, Onychodysplasia, Facial dysmorphism, and hypoTrichosis) syndrome (#MIM 614813), a very rare autosomal recessive Mendelian condition so far reported in 13 unrelated families 4‐12 . All except one of the described cases were caused by homozygous POC1A pathogenic variants.…”

Section: Introductionmentioning

confidence: 99%

Clinical presentation and molecular characterization of a novel patient with variant POC1A‐related syndrome

et al. 2021

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Biallelic pathogenic variants in POC1A result in SOFT (Short‐stature, Onychodysplasia, Facial‐dysmorphism, and hypoTrichosis) and variant POC1A‐related (vPOC1A) syndromes. The latter, nowadays described in only two unrelated subjects, is associated with a restricted spectrum of variants falling in exon 10, which is naturally skipped in a specific POC1A mRNA. The synthesis of an amount of a POC1A isoform from this transcript in individuals with vPOC1A syndrome has been believed as the likely explanation for such a genotype–phenotype correlation. Here, we illustrate the clinical and molecular findings in a woman who resulted to be compound heterozygous for a recurrent frameshift variant in exon 10 and a novel variant in exon 9 of POC1A. Phenotypic characteristics of this woman included severe hyperinsulinemic dyslipidemia, acanthosis nigricans, moderate growth restriction, and dysmorphisms. These manifestations overlap the clinical features of the two previously published individuals with vPOC1A syndrome. RT‐PCR analysis on peripheral blood and subsequent sequencing of the obtained amplicons demonstrated a variety of POC1A alternative transcripts that resulted to be expressed in the proband, in the healthy mother, and in controls. We illustrate the possible consequences of the two POC1A identified variants in an attempt to explain pleiotropy in vPOC1A syndrome.

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“…[25][26][27][28] Current studies assessing diagnostic yield of exome sequencing for syndromic short stature with prior negative karyotype, microarray and NGS targeted panels is reported between 16.5% and 46%. [29][30][31][32] Clinical genome sequencing has begun to be offered in select laboratories and can be considered if available. At this time, important considerations include the cost of this testing, insurance reimbursement, and lack of evidence that clinical genome sequencing has a significantly increased diagnostic yield compared with clinical exome sequencing.…”

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confidence: 99%

Focused Revision: ACMG practice resource: Genetic evaluation of short stature

Mintz

Seaver

Irons

et al. 2021

Genetics in Medicine

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with the following addendum as a Focused Revision:We conducted a comprehensive search of the literature published between 2009, when the previous guidelines were published, and May 2020. Keywords used in PubMed included "short stature," "genetic evaluation," "short stature microarray," "short stature exome sequencing" using [All Fields] [TITLE-ABS-KEY] criteria. A total of 583 articles were found of which 539 primarily addressed the identification of genes associated with growth and gene defects associated with short stature. There were 44 articles regarding the genetic evaluation of short stature. We reviewed these articles and provide the following focused revision to the original document.

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Genetic Disorders in Prenatal Onset Syndromic Short Stature Identified by Exome Sequencing

Cited by 44 publications

References 33 publications

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann‐Steiner syndrome

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann‐Steiner syndrome

Clinical presentation and molecular characterization of a novel patient with variant POC1A‐related syndrome

Focused Revision: ACMG practice resource: Genetic evaluation of short stature

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