Translating principles of precision medicine into speech-language pathology: Clinical trial of a proactive speech and language intervention for infants with classic galactosemia

Peter, Beate; Davis, Jennifer; Finestack, Lizbeth H.; Stoel‐Gammon, Carol; VanDam, Mark; Bruce, Laurel; Kim, Yookyung; Eng, Linda; Cotter, Sarah; Landis, Emily K.; Beames, Sam; Scherer, Nancy J.; Knerr, Ina; Williams, Delaney; Schrock, Claire; Potter, Nancy L.

doi:10.1016/j.xhgg.2022.100119

Cited by 11 publications

(7 citation statements)

References 81 publications

(114 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is currently undergoing clinical trial in a cohort of infants with a newborn diagnosis of classic galactosemia, an inborn error of metabolism that puts children at risk for severe speech and language disorders. Pilot results are consistent with beneficial effects (Peter et al, 2021, 2022; Peter, Potter, et al, 2019). Similar strategies can be trialed in infants with deleterious BCL11A variants to investigate whether the most commonly observed BCL11A‐IDD traits can be mitigated or even prevented.…”

Section: Discussionsupporting

confidence: 71%

Three children with different de novo BCL11A variants and diverse developmental phenotypes, but shared global motor discoordination and apraxic speech: Evidence for a functional gene network influencing the developing cerebellum and motor and auditory cortices

Bruce

Peter

2022

American J of Med Genetics Pt A

Self Cite

View full text Add to dashboard Cite

BCL11A is implicated in BCL11A-Related Intellectual Development Disorder (BCL11A-IDD). Previously reported cases had various types of BCL11A variants (copy-number variations [CNVs], singlenucleotide variants [SNVs]). Phenotypes included global, cognitive, and motor delays, autism spectrum disorder (ASD), craniofacial dysmorphology, and speech and language delays described generally, with only two reports specifying childhood apraxia of speech (CAS). Here, we present three additional children with CAS and de novo BCL11A variants, a p.Ala182Thr nonconservative missense and a p.GLu611.Ter nonsense variant, both in exon 4, and a 106 kb deletion harboring exons 1 and 2. All three children have fine and gross motor discoordination, feeding difficulties, and visual motor disorders. Intellectual and learning disabilities and disordered language skills were seen only in the child with the missense variant and the child with the deletion. These findings align with, and expand, previous findings in that BCL11A variants have significant and highly penetrant apraxic effects across motor systems, consistent with cerebellar involvement. The deletion of exons 1 and 2 is the smallest BCL11A CNV with the full phenotypic expression reported to date. The present results support previous findings in that BCL11A-IDD can result from BCL11A variants regardless of type (deletion, SNVs).A gene expression study shows that BCL11 is expressed highly in the early developing cerebellum and primary motor and auditory cortices. Significant co-expression rates in these regions with genes previously implicated in disorders of spoken language and in ASD support the phenotypic overlaps in children with BCL11A-IDD, CAS, and ASD.

show abstract

Section: Discussionsupporting

confidence: 71%

Three children with different de novo BCL11A variants and diverse developmental phenotypes, but shared global motor discoordination and apraxic speech: Evidence for a functional gene network influencing the developing cerebellum and motor and auditory cortices

Bruce

Peter

2022

American J of Med Genetics Pt A

Self Cite

View full text Add to dashboard Cite

show abstract

“…A better understanding of the genotype–phenotype associations regarding communication and motor skills can lead to the development of proactive interventions based on an early genetic diagnosis instead of overt manifestations of deficits that typically cannot be diagnosed until children are older, for example, age 2–3 years for disorders of speech and language. An example of such an intervention is the Babble Boot Camp©, designed for infants at predictable risk for speech and language disorders based on a newborn diagnosis of classic galactosemia and confirmation with genotyping (Peter et al, 2019, 2021, 2022). The intervention is implemented by a speech‐language pathologist via parent training, with a focus on precursor and earliest communication skills.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, this latter set of traits presents an opportunity for novel and designed for infants at predictable risk for speech and language PETER disorders based on a newborn diagnosis of classic galactosemia and confirmation with genotyping (Peter et al, 2019(Peter et al, , 2021(Peter et al, , 2022…”

Section: Discussionmentioning

confidence: 99%

A case with cardiac, skeletal, speech, and motor traits narrows the subtelomeric 19p13.3 microdeletion region to 46 kb

Peter

2022

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Subtelomeric 19p13.3 deletions have been associated with diverse anatomical and developmental phenotypes. A recent study of eight patients with subtelomeric interstitial 19p13.3 microdeletions at 0.3–1.4 Mb (hg 19) showed associations with growth restrictions, skeletal deformities, craniofacial anomalies, congenital heart defects, renal malformations, hernias, immune system deficits, fine and gross motor delays, speech delays, and developmental and learning delays. The authors defined two small regions of overlap containing four and 11 genes, respectively, with potential haploinsufficiency. Here, we present a new case with a de novo 184 kb deletion containing eight genes, three of which fall into the second previously identified small region of overlap, reducing the shared region to 46 kb. Phenotypic traits include most of the core findings in the previously reported cases but not growth restrictions, craniofacial anomalies, renal malformation, and learning disability. A closer look at the speech and motor delays reveals apraxic speech and discoordination in the fine and gross motor domain, consistent with cerebellar involvement across motor systems. Findings are consistent with a role of AZU1 in the observed immune deficiencies and PTBP1 in the observed skeletal, abdominal, speech, language, motor, and sensory traits. This case thus contributes to a more nuanced understanding of the subtelomeric 19p13.3 deletion region.

show abstract

“…Adding more diverse modalities may allow data-fusion models to gain even more insight and potentially identify DD and other disorders faster and more accurately than providers and physicians given the right data. This could lead to earlier diagnosis, new treatment approaches that are proactive and personalized, and better health, a translation of principles of precision medicine that is already in progress regarding disorders of spoken language (68). Precision medicine is just one of many fields that can benefit greatly due to the advances of data-fusion and other advanced ML techniques.…”

Section: Conclusion and Future Studiesmentioning

confidence: 99%

A data-fusion approach to identifying developmental dyslexia from multi-omics datasets

Carrion

Nandakumar

Shi

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

This exploratory study tested and validated the use of data fusion and machine learning techniques to probe high-throughput omics and clinical data with a goal of exploring the etiology of developmental dyslexia. Developmental dyslexia is the leading learning disability in school aged children affecting roughly 5-10% of the US population. The complex biological and neurological phenotype of this life altering disability complicates its diagnosis. Phenome, exome, and metabolome data was collected allowing us to fully explore this system from a behavioral, cellular, and molecular point of view. This study provides a proof of concept showing that data fusion and ensemble learning techniques can outperform traditional machine learning techniques when provided small and complex multi-omics and clinical datasets. Heterogenous stacking classifiers consisting of single-omic experts/models achieved an accuracy of 86%, F1 score of 0.89, and AUC value of 0.83. Ensemble methods also provided a ranked list of important features that suggests exome single nucleotide polymorphisms found in the thalamus and cerebellum could be potential biomarkers for developmental dyslexia and heavily influenced the classification of DD within our machine learning models.

show abstract

Translating principles of precision medicine into speech-language pathology: Clinical trial of a proactive speech and language intervention for infants with classic galactosemia

Cited by 11 publications

References 81 publications

Three children with different de novo BCL11A variants and diverse developmental phenotypes, but shared global motor discoordination and apraxic speech: Evidence for a functional gene network influencing the developing cerebellum and motor and auditory cortices

Three children with different de novo BCL11A variants and diverse developmental phenotypes, but shared global motor discoordination and apraxic speech: Evidence for a functional gene network influencing the developing cerebellum and motor and auditory cortices

A case with cardiac, skeletal, speech, and motor traits narrows the subtelomeric 19p13.3 microdeletion region to 46 kb

A data-fusion approach to identifying developmental dyslexia from multi-omics datasets

Contact Info

Product

Resources

About