Genetic Puzzle Solved: How a Missing DNA Segment Triggers Rare Facial Syndrome

Unraveling a Rare Genetic Mystery

In a groundbreaking discovery published in npj Genomic Medicine, researchers have uncovered a novel mechanism behind Teebi-hypertelorism syndrome 1 (TBHS1), a rare condition characterized by distinctive facial features. The study reveals how an intragenic deletion disrupting the SPECC1L gene’s translation initiation leads to the production of abnormal proteins, offering new insights into craniofacial development disorders.

Unraveling a Rare Genetic Mystery
The Clinical Presentation: Father and Son Case Study
Genetic Analysis Reveals Complex Inheritance
Novel Pathogenic Mechanism: Alternative Translation Initiation
Context Within Known TBHS1 Cases
Broader Implications for Genetic Medicine

The Clinical Presentation: Father and Son Case Study

The research centered on a two-year-old male presenting with speech and language delay, along with remarkable craniofacial features including midface retrusion, significant hypertelorism (exceptionally wide-spaced eyes), telecanthus, micrognathia, recurrent joint dislocations, and anterior segment eye dysgenesis. His head circumference measured at the 76th percentile, and follow-up at ages 6-7 showed no developmental or learning concerns.

Review of paternal childhood photographs revealed similar craniofacial characteristics, notably wide-spaced eyes and relative macrocephaly. The father, who didn’t experience developmental delays, saw his hypertelorism become less pronounced in adulthood but was diagnosed with Axenfeld Rieger anomaly, an eye disorder. This familial pattern provided crucial clues for genetic investigation., according to industry developments

Genetic Analysis Reveals Complex Inheritance

Whole genome sequencing identified two paternally inherited variants of unknown significance: a heterozygous 7.7 kb deletion at chromosome 22q11.23 affecting SPECC1L exon 3, and a FOXC1 gene substitution. While the FOXC1 variant likely explains the father’s eye anomaly, researchers determined it couldn’t account for the characteristic TBHS1 features, suggesting the family carries two separate genetic conditions., according to recent innovations

The SPECC1L deletion proved particularly significant as it encompasses exon 3, which contains the gene’s canonical translation start site (ATG codon) and encodes the protein’s first 51 amino acids. This deletion affects the MANE transcript and five of six annotated transcripts, making it a prime candidate for explaining the TBHS1 phenotype., according to expert analysis

Novel Pathogenic Mechanism: Alternative Translation Initiation

Researchers hypothesized that deleting the start-codon containing exon might force the cellular machinery to use alternative downstream methionines for translation initiation. Computational predictions identified potential alternative in-frame ATG sites with even stronger Kozak sequence similarity scores than the canonical start codon., as as previously reported, according to technology trends

Experimental validation using transfected HEK293T cells revealed dramatic differences in protein expression. Wild-type SPECC1L produced a single 160 kDa band, while the mutant construct generated two shorter bands at approximately 150 kDa and 130 kDa. The 150 kDa band likely results from translation initiation at a downstream ATG in exon 4, while the 130 kDa isoform may originate from an even later start site or through proteolytic cleavage., according to recent developments

Notably, both truncated protein forms appeared more abundant than the wild-type protein, suggesting increased translation efficiency or stability. Immunofluorescent staining confirmed both proteins maintained cytoplasmic localization, though mutant proteins showed subtle differences in distribution patterns that warrant further investigation.

Context Within Known TBHS1 Cases

The research team reviewed 44 previously reported individuals from 22 families with TBHS1 phenotypes, carrying 17 distinct SPECC1L variants. Most were missense mutations clustered within specific protein domains (CCD2 and CHD), with only three recurrent across independent families.

Comparison with previously reported features reveals:

Craniofacial abnormalities are most prevalent, including prominent forehead, high arched eyebrows, and wide nasal features
Neurodevelopmental delay or intellectual disability affects approximately half of reported cases
Cleft lip/palate occurs in only 23% of individuals
Central nervous system abnormalities, particularly ventriculomegaly and corpus callosum anomalies, appear in about two-thirds of imaged cases

Broader Implications for Genetic Medicine

This study demonstrates how intragenic deletions affecting translation initiation can cause human disease through novel mechanisms beyond simple protein truncation. The discovery that alternative translation start sites can produce stable, potentially functional protein isoforms expands our understanding of genetic disorder pathogenesis.

The findings highlight the importance of considering non-canonical translation mechanisms when interpreting genetic variants, particularly in cases where deletions affect start codons. This knowledge could improve diagnostic accuracy and eventually inform therapeutic strategies for SPECC1L-related disorders and similar conditions caused by translation initiation disruptions.

Future research directions include investigating the functional consequences of the truncated SPECC1L isoforms under physiological conditions and exploring whether similar mechanisms operate in other genetic disorders involving start codon disruptions.