Objective To introduce the pathophysiological Tulip classification system for underlying cause and mechanism of perinatal mortality based on clinical and pathological findings for the purpose of counselling and prevention.Design Descriptive.Setting Tertiary referral teaching hospital.Population Perinatally related deaths.Methods A classification consisting of groups of cause and mechanism of death was drawn up by a panel through the causal analysis of the events related to death. Individual classification of cause and mechanism was performed by assessors. Panel discussions were held for cases without consensus.Main outcome measures Inter-rater agreement for cause and mechanism of death.Results The classification consists of six main causes with subclassifications: (1) congenital anomaly (chromosomal, syndrome and single-or multiple-organ system), (2) placenta (placental bed, placental pathology, umbilical cord complication and not otherwise specified [NOS]), (3) prematurity (preterm prelabour rupture of membranes, preterm labour, cervical dysfunction, iatrogenous and NOS), (4) infection (transplacental, ascending, neonatal and NOS), (5) other (fetal hydrops of unknown origin, maternal disease, trauma and out of the ordinary) and (6) unknown. Overall kappa coefficient for agreement for cause was 0.81 (95% CI 0.80-0.83). Six mechanisms were drawn up: cardio/circulatory insufficiency, multi-organ failure, respiratory insufficiency, cerebral insufficiency, placental insufficiency and unknown. Overall kappa for mechanism was 0.72 (95% CI 0.70-0.74).Conclusions Classifying perinatal mortality to compare performance over time and between centres is useful and necessary. Interpretation of classifications demands consistency. The Tulip classification allows unambiguous classification of underlying cause and mechanism of perinatal mortality, gives a good inter-rater agreement, with a low percentage of unknown causes, and is easily applicable in a team of clinicians when guidelines are followed.

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KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.

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Parents should be counseled on aspects of cytogenetic analysis after fetal death. We advise performing nonselective invasive testing after fetal death and before labor for all fetal deaths.

A series of 44 unrelated patients in whom COL2A1 screening demonstrated normal results but whose phenotype was nevertheless highly suggestive of either Stickler syndrome (with ocular involvement) or Marshall syndrome were investigated for mutations in the COL11A1 gene. Heterozygous COL11A1 mutations were found in 10 individuals. A splice site alteration (involving introns 47-55) was present in seven cases, with one in intron 50 (c.3816 + 1G > A) occurring in three patients. Two patients had a different deletion, and a missense mutation (Gly1471Asp) was observed in one case. In 4/10 patients the phenotype was classified as Marshall syndrome because of early-onset severe hearing loss and characteristic facial features. These four patients were all heterozygous for a splice site mutation in intron 50. One of these cases had a type 1 vitreous anomaly despite the presence of a COL11A1 mutation. The remaining 6/10 patients had an overlapping Marshall-Stickler phenotype with less pronounced facial features. None of these had a mutation in the hot spot region of intron 50.

Perinatal death (PD) is a devastating obstetric complication. Determination of cause of death helps in understanding why and how it occurs, and it is an indispensable aid to parents wanting to understand why their baby died and to determine the recurrence risk and management in subsequent pregnancy. Consequently, a perinatal death requires adequate diagnostic investigation. An important first step in the analysis of PD is to identify the case circumstances, including relevant details regarding maternal history, obstetric history and current pregnancy (complications are evaluated and recorded). In the next step, placental examination is suggested in all cases, together with molecular cytogenetic evaluation and fetal autopsy. Investigation for fetal-maternal hemorrhage by Kleihauer is also recommended as standard. In cases where parents do not consent to autopsy, alternative approaches such as minimally invasive postmortem examination, postmortem magnetic resonance imaging, and fetal photographs are good alternatives. After all investigations have been performed it is important to combine findings from the clinical review and investigations together, to identify the most probable cause of death and counsel the parents regarding their loss.

Objective Conventional genetic tests (quantitative fluorescent‐PCR [QF‐PCR] and single nucleotide polymorphism‐array) only diagnose ~40% of fetuses showing ultrasound abnormalities. Rapid exome sequencing (rES) may improve this diagnostic yield, but includes challenges such as uncertainties in fetal phenotyping, variant interpretation, incidental unsolicited findings, and rapid turnaround times. In this study, we implemented rES in prenatal care to increase diagnostic yield. Methods We prospectively studied 55 fetuses. Inclusion criteria were: (a) two or more independent major fetal anomalies, (b) hydrops fetalis or bilateral renal cysts alone, or (c) one major fetal anomaly and a first‐degree relative with the same anomaly. In addition to conventional genetic tests, we performed trio rES analysis using a custom virtual gene panel of ~3850 Online Mendelian Inheritance in Man (OMIM) genes. Results We established a genetic rES‐based diagnosis in 8 out of 23 fetuses (35%) without QF‐PCR or array abnormalities. Diagnoses included MIRAGE (SAMD9), Zellweger (PEX1), Walker‐Warburg (POMGNT1), Noonan (PTNP11), Kabuki (KMT2D), and CHARGE (CHD7) syndrome and two cases of Osteogenesis Imperfecta type 2 (COL1A1). In six cases, rES diagnosis aided perinatal management. The median turnaround time was 14 (range 8‐20) days. Conclusion Implementing rES as a routine test in the prenatal setting is challenging but technically feasible, with a promising diagnostic yield and significant clinical relevance.