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Ali Alsuheel Asseri,1 Ahmad A Alzoani,2 Mohammed Almahdi,3 Hussein Almahdi,4 Nouf Almushayt,3 Noha Saad Alyazidi,3 Basmah Mohammed Al Mufarrih5 1Department of Child Health, King Khalid University, Abha, 61421, Saudi Arabia; 2Department of Neonatology, Abha Maternity and Children Hospital, Ministry of Health, Abha, 62521, Saudi Arabia; 3Department of Pediatrics, Abha Maternity and Children Hospital, Ministry of Health, Abha, 62521, Saudi Arabia; 4College of Medicine, King Khalid University, Abha, 61421, Saudi Arabia; 5Department of Obstetrics and Gynecology, Abha Maternity and Children Hospital, Ministry of Health, Abha, 62521, Saudi ArabiaCorrespondence: Ali Alsuheel Asseri, Department of Child Health, College of Medicine, King Khalid University, Abha, Saudi Arabia, Tel +966500186013, Fax +9662418139, Email alsoheel11@kku.edu.saAbstract: Jeune syndrome, or asphyxiating thoracic dystrophy (JATD), is a rare autosomal recessive skeletal dysplasia with heterogeneous genetic and clinical phenotypes, which primarily affects cartilage and bone development. Herein, we report a patient with a lethal form of SRTD3 without polydactyly (JATD), which led to severe restrictive lung disease and fatal respiratory failure. A full-term boy was born to a 30-year-old mother who was known to have hypothyroidism and was on thyroxine. The parents were first-degree cousins and had one healthy older son. Fetal ultrasound showed a cephalic fetus, normal amniotic fluid and a fundal placenta. All long bones and ribs were below the 1% percentile. The femur was bowed with no fractures or signs of significant demineralization at time of imaging. Head and abdominal circumference were within normal range. An echocardiogram on the 2nd day of life showed severe pulmonary hypertension (PHTN). Nitric oxide was started due to the presence of persistent hypoxia and severe PHTN. The patient continued to require high cardiorespiratory support, but the medical condition worsened, and respiratory failure persisted. The patient died of severe respiratory failure at 16 days of life due to respiratory insufficiency secondary to a severely restricted thoracic cage. Whole-exome sequencing (WES) revealed a homozygous mutation in the DYNC2H1 (NM_001377.3) gene, namely, the c.9041G>T NP_001368.2: p.(Arg3014Ile) missense variant, which results in the substitution of the arginine codon at amino acid position 3014 with an isoleucine codon. The phenotyping of the patient’s JATD and the detection of a homozygous variant in the DYNC2H1 gene confirmed the diagnosis of short-rib thoracic dysplasia-3 without polydactyly. In summary, the patient had isolated skeletal anomalies without polydactyly or other organ involvement. Additionally, the infant had severe PHTN on top of the respiratory failure, which eventually caused death. Considerably more work will need to be done to determine the clinical spectrum of JATD and understand its genetic heterogeneity.Keywords: SRTD3, Jeune syndrome, asphyxiating thoracic dystrophy, DYNC2H1

Objective: We present the perinatal imaging findings and molecular genetic analysis in a fetus with short-rib polydactyly syndrome (SRPS) type III or short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3). Case report: A 29-year-old, primigravid woman was referred for genetic counseling at 15 weeks of gestation because of abnormal ultrasound findings of short limbs, a narrow chest and bilateral polydactyly of the hands and feet, consistent with a diagnosis of SRPS type III. Chorionic villus sampling was performed, and targeted next-generation sequencing (NGS) was applied to analyze a panel of 25 genes including CEP120, DYNC2H1, DYNC2LI1, EVC, EVC2, FGFR2, FGFR3, HOXD10, IFT122, IFT140, IFT172, IFT52, IFT80, KIAA0586, NEK1, PAPSS2, SLC26A2, SOX9, TCTEX1D2, TCTN3, TTC21B, WDR19, WDR34, WDR35 and WDR60. The NGS analysis identified novel mutations in the DYNC2H1 gene. The fetus was compound heterozygous for a missense mutation c.8077G > T (p.Asp2693Tyr) of paternal origin in DYNC2H1 and a frameshift mutation c.11741_11742delTT (p.Phe3914X) of maternal origin in DYNC2H1. The fetus had a karyotype of 46,XY, and postnatally manifested characteristic SRPS type III phenotype. Conclusion: Targeted NGS is useful in genetic diagnosis of fetal skeletal dysplasia and SRPS, and the information acquired is helpful in genetic counseling.